The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney
Open accessAbstract
The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.
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Written from the paper’s full text.
TL;DR
IL-17 induces renal Kallikrein-Kinin System components, especially Klk1, during disseminated *Candida albicans* infection, and this pathway protects the kidney by limiting apoptosis and preserving renal function independently of fungal clearance. Bradykinin treatment, alone or with low-dose fluconazole, improves survival in infected mice.
Key findings
- Microarray, qPCR, and immunoblotting showed renal Klk1/Klk1b27 expression was upregulated in infected WT kidney in an IL-17-dependent manner and suppressed in IL-17RA−/− mice; Klk1 was constitutively low in sham-infected WT and IL-17RA−/− kidneys but increased after *C. albicans* infection in WT.
- Adenoviral Klk1 overexpression significantly improved survival of *C. albicans*-infected IL-17RA−/− and WT mice, with little impact on renal inflammatory gene expression or fungal load.
- Bradykinin delayed mortality in IL-17RA−/− mice, in which 90% of untreated mice succumbed by day 5 post-infection, and Bdkrb1/Bdkrb2 antagonists significantly reduced survival in WT mice.
- Bradykinin preserved renal function in WT mice at day 7 post-infection, with significantly lower serum BUN and creatinine, reduced tubular damage and NGAL, and reduced apoptosis of kidney-resident cells; combining bradykinin with a minimally effective fluconazole dose (5 mg/kg) significantly improved survival versus either agent alone.
Methods
- Mouse disseminated candidiasis model using WT C57BL/6J and IL-17RA−/− mice infected intravenously with *C. albicans* strains CAF2-1 or SC5314, generally 1×10^5 cfu unless otherwise indicated; survival assessed over 14 days, with kidney fungal burden, histology, immunohistochemistry, flow cytometry, qPCR, Western blotting, and microarray profiling.
- In vitro assays used primary renal tubular epithelial cells (RTEC), bone marrow-derived macrophages, and bone marrow neutrophils treated with IL-17A, TNFα, IL-17C, IL-17F, bradykinin, or LPS; fungal killing was measured by cfu.
- Interventions included adenoviral overexpression of IL-17 or Klk1, bradykinin (300 nmol/kg/day), Bdkrb1 antagonist R715 (1 mg/kg/day), Bdkrb2 antagonist HOE140 (1 mg/kg/day), and fluconazole (5, 10, 20, or 40 mg/kg); statistical analyses used Kaplan-Meier, ANOVA, Mann-Whitney, or unpaired Student’s t tests with P<0.05 considered significant.
Limitations
- The paper states that serum creatinine and BUN did not correlate with survival benefit at late time points, and the basis is unclear; proposed explanations include bradykinin’s very short half-life (~30 sec), receptor internalization, negative feedback increasing bradykinin degradation by angiotensin-converting enzymes, and bradykinin effects on podocyte permeability.
- The paper states that the relative contributions of Bdkrb1 and Bdkrb2, and the role of PARs, in IL-17-Klk1-mediated renal protection remain unknown; it also notes that further studies should examine Klk gene expression in TNFα-deficient mice.
- Evident from the text: all experimental evidence comes from mouse models, primarily male C57BL/6J mice, with no human clinical data; bradykinin dosing, route, and safety/translation to patients are not established.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 65 cited sources checked · 0 supported · 0 flagged
- Findingown data
Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner.
“Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner.”
Quote in the paperSubstantial claim - Findingcitation
IL-17RA-/- mice demonstrated significantly increased kidney fungal burden compared to WT following C. albicans infection.
“Confirming previous reports, IL-17RA-/- mice demonstrated significantly increased kidney fungal burden in comparison to WT following infection with C. albicans (CAF2-1 or SC5314) (Fig 1A) [14,16,33].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- cites [16] FL van de Veerdonk, 2010, Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure, Shock source
Not checked in the free run.
- cites [33] AV Garg, 2015, MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation, Immunity source
Not checked in the free run.
- Findingown data
Overexpression of Klk1 restored protective renal immunity against systemic C. albicans infection in IL-17RA-/- mice.
“Moreover, overexpression of Klk1 restored protective renal immunity against systemic C. albicans infection in IL-17RA-/- mice.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Klk1 rescued IL-17RA-/- mice from candidiasis.
“Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis.”
- Also stated in: § Klk1 is required for IL-17-mediated renal protection against disseminated candidiasis · plain
“Remarkably, overexpression of Klk1 significantly improved the survival of C. albicans-infected IL-17RA-/- mice and in WT mice (Fig 2D).”
Quote in the paperSubstantial claim - Also stated in: § Klk1 is required for IL-17-mediated renal protection against disseminated candidiasis · plain
- Findingown data
Treatment with bradykinin rescued IL-17RA-/- mice from candidiasis.
“Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis.”
- Also stated in: § Activation of the bradykinin receptors is required for IL-17-Klk1 axis-driven protection against disseminated candidiasis · plain
“mortality in IL-17RA-/- mice was delayed with bradykinin treatment (Fig 3A).”
Quote in the paperSubstantial claim - Also stated in: § Activation of the bradykinin receptors is required for IL-17-Klk1 axis-driven protection against disseminated candidiasis · plain
- Findingown data
Mice lacking IL-17RA exhibited diminished Klk expression in the kidney.
“Mice lacking the IL-17 receptor A subunit (IL-17RA) exhibited diminished Klk expression in the kidney.”
- Also stated in: § IL-17 triggers Klk expression in the kidney during disseminated candidiasis · plain
“Multiple Klk genes were suppressed in the kidney of IL-17RA-/- mice compared to WT following C. albicans infection.”
Quote in the paperSubstantial claim - Also stated in: § IL-17 triggers Klk expression in the kidney during disseminated candidiasis · plain
- Findingown data
Combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone in disseminated candidiasis.
“Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone.”
Quote in the paperSubstantial claim - Findingown data
Differences in Klk expression between WT and IL-17RA-/- are not due to differential fungal loads.
“Either dose caused comparable Klk1 expression (S1B Fig), indicating that the differences in Klk expression are not due to differential fungal loads.”
Quote in the paperSubstantial claim - Findingown data
Cleaved Caspase-3 is localized in renal cortex and outer medullary region of untreated mice.
“Moreover, IHC indicated that cleaved Caspase-3 is localized in the renal cortex and outer medullary region of untreated mice (Fig 6D).”
Quote in the paperNot a substantial claim - Findingown data
Bradykinin-treated mice demonstrated significantly diminished serum BUN and creatinine levels compared to untreated animals.
“Mice treated with bradykinin demonstrated significantly diminished serum blood urea nitrogen and creatinine levels compared to untreated animals (Fig 4D), indicating that bradykinin preserves normal renal function in systemic C. albicans infection.”
Quote in the paperSubstantial claim - Findingown data
Mice infected with Ad-IL-17 exhibited 400-fold more serum IL-17 than control.
“Mice infected with Ad-IL-17 exhibited 400-fold more serum IL-17 than with a control vector (Ad-ctrl) (S2A Fig).”
Quote in the paperSubstantial claim - Findingown data
Bradykinin induced IL-6 in RTECs in vitro.
“Bradykinin induced IL-6 in RTECs (Fig 5D), but did not induce IL-6, TNFα or nitrite in BMDMs (Fig 5E and 5F).”
Quote in the paperSubstantial claim - Findingown data
Lower expression of renal Klk1 in the absence of IL-17RA during systemic infection.
“Confirming the gene expression data, we observed lower expression of renal Klk1 in the absence of IL-17RA during systemic infection (Fig 1E and 1F).”
Quote in the paperSubstantial claim - Findingown data
Bradykinin treatment significantly reduced number of TUNEL positive cells in renal cortex.
“Concurrently, there was a significant reduction in the number of TUNEL positive cells in the renal cortex following bradykinin treatment (Fig 6B).”
Quote in the paperSubstantial claim - Findingown data
Classical IL-17-responsive genes Cxcl1, Cxcl2, and Lcn2 were unaffected in IL-17RA-/- mice during candidiasis.
“The expression of classical IL-17-responsive genes such as Cxcl1, Cxcl2 and Lcn2 were unaffected in IL-17RA-/- mice (S1A Fig).”
Quote in the paperSubstantial claim - Findingown data
Percentages of kidney infiltrating inflammatory cells (CD45+), neutrophils (Gr1+), and macrophages (F4/80+) were similar between bradykinin-treated and untreated groups.
“In agreement with the fungal clearance rates, the percentages of kidney infiltrating inflammatory cells (CD45+), neutrophils (Gr1+) and macrophages (F4/80+) were similar between groups (Fig 5B and S3B Fig).”
Quote in the paperSubstantial claim - Findingown data
Bradykinin-treated cohort exhibited significantly delayed mortality compared to untreated control.
“Indeed, the bradykinin-treated cohort exhibited significantly delayed mortality compared to an untreated control group (Fig 4A and 4B).”
Quote in the paperSubstantial claim - Findingown data
Only kidney-resident cells, particularly RTEC, expressed Klk1 during C. albicans infection.
“Only kidney-resident cells, particularly renal tubular epithelial cells (RTEC), expressed Klk1 during infection (Fig 2A).”
Quote in the paperSubstantial claim - Findingown data
Mice given Bdkrb1 and Bdkrb2 antagonists had significantly reduced survival compared to untreated controls following systemic C. albicans infection.
“Mice given Bdkrb1 and Bdkrb2 antagonists had significantly reduced survival compared to untreated controls (Fig 3B).”
Quote in the paperSubstantial claim - Findingown data
Influx of inflammatory cells was comparable between bradykinin-treated and untreated infected mice.
“Interestingly, the influx of inflammatory cells was comparable between the treated and untreated groups.”
Quote in the paperSubstantial claim - Findingown data
In C. albicans-infected WT mice, treatment with the combination of bradykinin and FLC significantly increased survival compared to untreated mice or mice given FLC or bradykinin alone.
“mice receiving the combination of bradykinin and FLC showed a significant increase in survival compared to untreated mice or mice given FLC or bradykinin alone (Fig 7B).”
Quote in the paperSubstantial claim - Findingown data
Mice treated with bradykinin did not show an increased incidence of angioedema at day 7 p.i.
“mice treated with bradykinin did not show an increased incidence of angioedema at day 7 p.i. (Fig 4C).”
Quote in the paperSubstantial claim - Findingown data
Expression of NGAL was significantly diminished in bradykinin-treated animals.
“Furthermore, we observed significantly diminished expression of neutrophil gelatinase-associated lipocalin (NGAL), a prototypical kidney injury marker, in bradykinin treated animals (Fig 4F and 4G).”
Quote in the paperSubstantial claim - Findingown data
IL-17 preserves kidney function during C. albicans invasion.
“IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during C. albicans invasion (S6 Fig).”
Quote in the paperSubstantial claim - Findingown data
IL-17 and TNFα triggered strong synergistic upregulation of Klk1 and Klk1b27 mRNA in primary RTEC.
“Indeed, IL-17 and TNFα triggered strong synergistic upregulation of Klk1 and Klk1b27 mRNA (Fig 2B).”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences in expression of genes encoding tissue-protective growth factors (Hgf, Ctgf) or matrix-metalloproteinases (Mmp2, Mmp9) at day 7 p.i. between bradykinin-treated and untreated mice.
“Additionally, there were no significant differences in expression of genes encoding tissue-protective growth factors (Hgf and Ctgf) or matrix-metalloproteinases at day 7 p.i. (Mmp2 and Mmp9) (S4B Fig).”
Quote in the paperNot a substantial claim - Findingown data
Neither IL-17F nor IL-17C induced the expression of Klk genes in RTEC.
“Neither IL-17F nor IL-17C induced the expression of Klk genes (S1C Fig).”
Quote in the paperSubstantial claim - Findingown data
Fungal loads were comparable between bradykinin-treated and untreated groups at days 3 and 7 p.i.
“Although differences in kidney function were already evident early as day 7 p.i. (Fig 4D), fungal loads were comparable between the bradykinin treated and untreated groups at these time points (Fig 5A).”
Quote in the paperSubstantial claim - Findingown data
Genes encoding the KKS were enriched among differentially expressed genes in the kidney during candidiasis.
“Most striking to us based on their known role in kidney physiology was the enrichment of genes encoding the KKS (Fig 1B and 1C).”
Quote in the paperSubstantial claim - Findingown data
The overall renal gene expression profile in IL-17RA-/- mice during candidiasis is distinct from IL-17-dependent gene profiles in other settings.
“Although a few genes previously shown to be controlled by IL-17 were differentially expressed in the kidney during candidiasis, overall we saw a surprisingly distinct gene profile compared to analyses of IL-17-dependent genes in other settings (Fig 1B and S1A Fig) [18].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] HR Conti, 2009, Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis, J Exp Med source
Not checked in the free run.
- Findingown data
Bradykinin treatment significantly diminished number of cleaved Caspase-3+ kidney-resident cells (CD45-).
“In agreement with the reduced apoptosis (Fig 6A), bradykinin treatment resulted in a significantly diminished number of cleaved Caspase-3+ kidney-resident cells (CD45-) (Fig 6C).”
Quote in the paperSubstantial claim - Findingown data
Intraperitoneal injection of bradykinin in uninfected WT mice exerted only a very brief hypotensive response that peaked within ~1 minute with full recovery by 6 minutes (maximum reduction of Mean Arterial BP 36%).
“We find that i.p. injection of bradykinin exerted only a very brief hypotensive response that peaked within ~1 minute with full recovery by 6 minutes (maximum reduction of Mean Arterial BP was 36%) (S3A Fig).”
Quote in the paperSubstantial claim - Findingown data
Klk1 was upregulated in WT kidney following C. albicans infection.
“However, Klk1 was upregulated in WT kidney following C. albicans infection.”
Quote in the paperSubstantial claim - Findingown data
Bradykinin treatment significantly reduced frequency of early and late apoptotic kidney-resident cells (CD45-) at day 7 p.i.
“At day 7 p.i., flow cytometry analysis revealed a significantly reduced frequency of both early (AnnexinV+PI-) and late (AnnexinV+PI+) apoptotic kidney-resident cells (CD45-) in bradykinin treated compared to untreated mice (Fig 6A).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Klk1 significantly improved survival of C. albicans-infected IL-17RA-/- mice and WT mice.
“Remarkably, overexpression of Klk1 significantly improved the survival of C. albicans-infected IL-17RA-/- mice and in WT mice (Fig 2D).”
Quote in the paperSubstantial claim - Findingown data
Bradykinin treatment of BM-derived neutrophils and macrophages did not alter their ability to kill unopsonized C. albicans yeasts in vitro.
“Bradykinin treatment of BM-derived neutrophils and macrophages (BMDM) did not alter their ability to kill unopsonized C. albicans yeasts, as determined by an in vitro fungal killing assay (Fig 5C).”
Quote in the paperSubstantial claim - Findingown data
Bradykinin treatment resulted in minimal extracellular matrix protein deposition in candidiasis.
“We observed minimal extracellular matrix protein deposition in bradykinin treated mice (S4A Fig).”
Quote in the paperNot a substantial claim - Findingown data
In WT mice with disseminated candidiasis, the lowest dose of FLC (5 mg/kg) was the least effective in clearing the fungus at day 4 p.i.
“The lowest dose of FLC (5 mg/kg) was the least effective in clearing the fungus at day 4 p.i. (S5A Fig).”
Quote in the paperSubstantial claim - Findingown data
IL-17 prevents renal tissue damage during C. albicans invasion.
“IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during C. albicans invasion (S6 Fig).”
Quote in the paperSubstantial claim - Findingown data
Fungal clearance correlated well with survival in this model.
“Fungal clearance correlated well with survival, as mice treated with FLC (5 mg/kg) showed the same susceptibility as untreated animals (S5B Fig).”
Quote in the paperSubstantial claim - Findingown data
The paper identified renal-protective kallikreins as novel IL-17 target genes in systemic candidiasis.
“we have identified renal-protective kallikreins as novel IL-17 target genes in systemic candidiasis”
Quote in the paperSubstantial claim - Findingown data
Klk1 was constitutively expressed at comparable low levels in sham-infected WT and IL-17RA-/- mice.
“Klk1 was constitutively expressed at comparable, albeit low, levels in the sham-infected WT and IL-17RA-/- mice.”
Quote in the paperSubstantial claim - Findingown data
In WT mice with disseminated candidiasis, treatment with FLC at 5 mg/kg resulted in the same susceptibility as untreated animals.
“mice treated with FLC (5 mg/kg) showed the same susceptibility as untreated animals (S5B Fig).”
Quote in the paperSubstantial claim - Findingown data
Ad-IL-17 administration upregulated multiple IL-17 target genes in the kidney (Il6, Cxcl5, Lcn2).
“Additionally, Ad-IL-17 administration upregulated multiple IL-17 target genes in the kidney (Il6, Cxcl5 and Lcn2) (Suppl. Fig 2B).”
Quote in the paperSubstantial claim - Findingown data
IL-17 limits fungal growth in the kidney during C. albicans invasion.
“IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during C. albicans invasion (S6 Fig).”
Quote in the paperSubstantial claim - Findingown data
C. albicans-infected mice showed overt pathological changes in renal parenchyma characterized by loss of brush border epithelium and tubular atrophy at day 7 p.i., primarily in renal cortex and outer medullary region.
“the renal parenchyma of infected mice showed overt pathological changes characterized by loss of brush border epithelium and tubular atrophy at day 7 p.i. Moreover, the damage was primarily restricted to the renal cortex and outer medullary region.”
Quote in the paperSubstantial claim - Findingown data
Kidneys of Ad-IL-17-treated mice exhibited no overt inflammatory changes.
“Nonetheless, kidneys of Ad-IL-17-treated mice exhibited no overt inflammatory changes (S2C Fig).”
Quote in the paperNot a substantial claim - Findingown data
Renal damage was ameliorated upon bradykinin treatment.
“In line with the kidney function results, renal damage was ameliorated upon bradykinin treatment (Fig 4E).”
Quote in the paperSubstantial claim - Findingown data
Multiple Klk genes were suppressed in the kidney of IL-17RA-/- mice compared to WT following C. albicans infection.
“Multiple Klk genes were suppressed in the kidney of IL-17RA-/- mice compared to WT following C. albicans infection.”
Quote in the paperSubstantial claim - Findingown data
Extent of cleaved Caspase-3 was markedly reduced following bradykinin treatment.
“The extent of cleaved Caspase-3 was markedly reduced following bradykinin treatment (Fig 6D).”
Quote in the paperSubstantial claim - Findingown data
RTEC within the kidney stained positively for Klk1 following overexpression of IL-17.
“By IHC, RTEC within kidney stained positively for Klk1 following overexpression of IL-17.”
Quote in the paperSubstantial claim - Findingown data
IL-17 in conjunction with TNFα induces Klk1 gene in primary RTEC.
“we show that IL-17 (in conjunction with TNFα) induces Klk1 gene in primary RTEC”
Quote in the paperSubstantial claim - Findingown data
Combination therapy with bradykinin and low-dose FLC is effective in treating candidiasis in mice.
“we show proof-of-concept that combination therapy with bradykinin and low-dose FLC is effective in treating candidiasis in mice.”
Quote in the paperSubstantial claim - Findingreasoning
Therapeutic manipulation of the IL-17-KKS pathways protected mice from early mortality in disseminated candidiasis.
“therapeutic manipulation of the IL-17-KKS pathways protected mice from early mortality in disseminated candidiasis.”
Quote in the paperSubstantial claim - Findingcitation
The gene profile in C. albicans-infected kidney is surprisingly different compared to prior studies involving mucosal Candida infection such as the tongue.
“we were intrigued by the surprisingly different gene profile seen in C. albicans-infected kidney compared to prior studies involving mucosal Candida infection such as the tongue [18].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] HR Conti, 2009, Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis, J Exp Med source
Not checked in the free run.
- Findingnone given
Bradykinin at the dose levels used in this study did not exert long-term consequences on blood pressure.
“bradykinin at the dose levels used in this study did not seem to exert any long term consequences on blood pressure.”
Quote in the paperSubstantial claim - Findingown data
Mice treated with bradykinin did not show any signs of angioedema following fungal infection.
“mice treated with bradykinin did not show any signs of angioedema following fungal infection (Fig 4C).”
Quote in the paperSubstantial claim - Findingown data
Conserved C/EBPβ binding sites are present within the putative proximal promoters of the Klk1 gene.
“We have identified conserved CCAAT Enhancer Binding Protein (C/EBP)-β binding sites within the putative proximal promoters of the Klk1 gene”
Quote in the paperSubstantial claim - Findingcitation
Upregulation of transcripts encoding IL-17A and IL-17-responsive genes in the kidney has been observed.
“we and others have observed upregulation of transcripts encoding IL-17A and IL-17-responsive genes in the kidney [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- Findingown data
Serum creatinine and BUN levels did not correlate with the survival benefit at late time points.
“serum creatinine and BUN levels did not correlate with the survival benefit at late time points”
Quote in the paperSubstantial claim - Findingown data
The survival rate of mice treated with the combination therapy was similar to the survival rate in mice given four times the FLC dose.
“the survival rate of mice treated with the combination therapy was similar to the survival rate in mice given four times the FLC dose.”
Quote in the paperSubstantial claim - Findingown data
Bradykinin treatment improved renal function as early as 7 days p.i.
“Our data show that bradykinin treatment improved renal function as early as 7 days p.i.”
Quote in the paperSubstantial claim - Findingown data
Activation of the KKS pathway restored protection in IL-17RA-/- mice.
“Our data show that activation of the KKS pathway restored protection in IL-17RA-/- mice.”
Quote in the paperSubstantial claim - Premisecitation
Kininogens bind the C. albicans cell wall, causing the fungal SAP2 protease to induce release of biologically active kinins.
“Kininogens have been shown to bind the C. albicans cell wall, causing the fungal SAP2 protease to induce release of biologically active kinins [28,29].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28] G Bras, 2013, Release of biologically active kinin peptides, Met-Lys-bradykinin and Leu-Met-Lys-bradykinin from human kininogens by two major secreted aspartic proteases of Candida parapsilosis, Peptides source
Not checked in the free run.
- cites [29] O Bochenska, 2013, Secreted aspartic peptidases of Candida albicans liberate bactericidal hemocidins from human hemoglobin, Peptides source
Not checked in the free run.
- Interpretationown data
These data identify a previously unrecognized link between IL-17 and KKS-mediated renal protection against disseminated candidiasis.
“These data identify a previously unrecognized link between IL-17 and KKS-mediated renal protection against disseminated candidiasis, which may provide the basis for clinical intervention in this disease.”
Quote in the paperSubstantial claim - Interpretationown data
IL-17 prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the Kallikrein-Kinin System.
“These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS.”
Quote in the paperSubstantial claim - Interpretationown data
Therapeutic manipulation of IL-17-KKS pathways prevented apoptosis of renal cells following C. albicans infection.
“Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection.”
Quote in the paperSubstantial claim - Premisecitation
In C. albicans intravenous challenge in mice, the kidney is the most heavily colonized organ.
“In C. albicans intravenous challenge in mice, the kidney is the most heavily colonized organ [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] RD Leunk, 1979, Physiological and metabolic alterations accompanying systemic candidiasis in mice, Infect Immun source
Not checked in the free run.
- Interpretationown data
Addition of exogenous bradykinin in immunocompetent mice prevented renal damage by inhibiting apoptosis of kidney-resident cells.
“Addition of exogenous bradykinin in immunocompetent mice prevented renal damage by inhibiting apoptosis of kidney-resident cells, and prolonged animal survival during candidiasis.”
Quote in the paperSubstantial claim - Premisecitation
IL-17 is a key mediator of defense against candidiasis.
“IL-17 is a key mediator of defense against candidiasis.”
- Also stated in: § Introduction · hedged
“Considerable data implicate IL-17 (IL-17A) in immunity to C. albicans.”
- Also stated in: § Introduction · plain
“IL-17RA-/-, IL-17RC-/-, RORγt-/- and IL-17A-/- mice are all susceptible to systemic C. albicans infection [14–17].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- cites [15] E Bar, 2014, IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells, Immunity source
Not checked in the free run.
- cites [16] FL van de Veerdonk, 2010, Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure, Shock source
Not checked in the free run.
- cites [17] AW Ho, 2010, IL-17RC: a partner in IL-17 signaling and beyond, Semin Immunopathol source
Not checked in the free run.
- Also stated in: § Introduction · hedged
- Interpretationown data
IL-17 limits fungal growth in the kidney during disseminated candidiasis.
“These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS.”
Quote in the paperSubstantial claim - Premisecitation
During candidiasis, IL-17 is rapidly upregulated in the kidney.
“During candidiasis, IL-17 is rapidly upregulated in the kidney, but its function in that organ is unknown [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- Interpretationown data
Therapeutic manipulation of IL-17-KKS pathways prolonged survival following C. albicans infection.
“Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection.”
Quote in the paperSubstantial claim - Interpretationown data
Addition of exogenous bradykinin in immunocompetent mice prolonged animal survival during candidiasis.
“Addition of exogenous bradykinin in immunocompetent mice prevented renal damage by inhibiting apoptosis of kidney-resident cells, and prolonged animal survival during candidiasis.”
Quote in the paperSubstantial claim - Interpretationown data
IL-17 induces the Kallikrein-Kinin System in C. albicans-infected kidney.
“Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney”
- Also stated in: § Introduction · plain
“Here, we identified kallikrein genes as novel IL-17 targets in disseminated candidiasis, revealing an unanticipated link between IL-17 and KKS-mediated renal protection.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Interpretationown data
The Kallikrein-Kinin System provides significant renal protection in candidiasis.
“we show that the KKS provides significant renal protection in candidiasis.”
- Also stated in: § Introduction · hedged
“These data identify a previously unrecognized link between IL-17 and KKS-mediated renal protection against disseminated candidiasis, which may provide the basis for clinical intervention in this disease.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · hedged
- Interpretationown data
Therapeutic manipulation of IL-17-KKS pathways restored renal function following C. albicans infection.
“Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection.”
Quote in the paperSubstantial claim - Interpretationown data
IL-17 signaling in the kidney regulates Klk1 expression during disseminated candidiasis.
“Collectively, these data indicate that IL-17 signaling in the kidney regulates Klk1 expression during disseminated candidiasis.”
Quote in the paperSubstantial claim - Interpretationown data
A combination of bradykinin and FLC confers better protection against disseminated candidiasis than either drug individually.
“These data show that a combination of bradykinin and FLC confers better protection against disseminated candidiasis than either drug individually.”
Quote in the paperSubstantial claim - Interpretationreasoning
Use of bradykinin could potentially permit reducing the dose of antifungal drugs without compromising efficacy against fungal infection.
“Consequently, use of bradykinin could potentially permit reducing the dose of antifungal drugs without compromising efficacy against fungal infection.”
Quote in the paperSubstantial claim- Rests on an assumption: There is an unmet clinical need to reduce the dosage of current antifungal drugs to overcome drug resistance and toxicity.
- Interpretationown data
Bradykinin preserves renal function during systemic fungal infection by limiting apoptosis of kidney-resident cells.
“Thus, bradykinin preserves renal function during systemic fungal infection by limiting apoptosis of kidney-resident cells.”
Quote in the paperSubstantial claim - Interpretationown data
IL-17 induces the expression of Klk1 in RTEC following disseminated candidiasis.
“Thus, IL-17 induces the expression of Klk1 in RTEC following disseminated candidiasis.”
Quote in the paperSubstantial claim - Interpretationown data
Bdkrb signaling participates in renal host defense during disseminated candidiasis.
“Collectively, these results indicate participation of Bdkrb signaling in the renal host defense during disseminated candidiasis.”
Quote in the paperSubstantial claim - Premisecitation
Klk1 activates protease-activated receptors (PAR) such as PAR4 to trigger release of inflammatory mediators from RTEC.
“Additionally, Klk1 activates protease-activated receptors (PAR) such as PAR4 to trigger the release of inflammatory mediators from RTEC [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] WH Yiu, 2014, Tissue kallikrein mediates pro-inflammatory pathways and activation of protease-activated receptor-4 in proximal tubular epithelial cells, PLoS One source
Not checked in the free run.
- Interpretationown data
IL-17 in conjunction with TNFα directly regulates Klk gene expression in RTEC.
“Thus, IL-17 in conjunction with TNFα directly regulates Klk gene expression in RTEC, revealing a previously unrecognized class of IL-17-dependent target genes.”
Quote in the paperSubstantial claim - Interpretationown data
Bradykinin is not likely to have long-term consequences on renal function during candidiasis.
“This result indicates that bradykinin is not likely to have any long term consequences on renal function during candidiasis.”
Quote in the paperSubstantial claim - Interpretationown data
Bradykinin preserves normal renal function in systemic C. albicans infection.
“indicating that bradykinin preserves normal renal function in systemic C. albicans infection.”
Quote in the paperSubstantial claim - Interpretationown data
Defining the IL-17 anti-fungal pathway has highlighted a potentially translatable and testable approach to treating systemic candidiasis.
“defining the IL-17 anti-fungal pathway has highlighted a potentially translatable and testable approach to treating systemic candidiasis.”
Quote in the paperNot a substantial claim- Rests on an assumption: There is an unmet clinical need to reduce the dosage of current antifungal drugs to overcome drug resistance and toxicity.
- Interpretationown data
Bradykinin toxicity is unlikely.
“these studies argue against the likelihood of bradykinin toxicity”
Quote in the paperSubstantial claim - Interpretationreasoning
Lessons derived from studies of anti-C. albicans immunity at mucosal sites cannot always be applied to local kidney immune responses.
“lessons derived from studies of anti-C. albicans immunity at mucosal sites cannot always be applied to local kidney immune responses.”
Quote in the paperSubstantial claim - Premisecitation
Mice deficient in specific PARs or treated with PAR antagonists exhibited compromised renal inflammatory changes.
“Mice deficient in specific PARs or treated with PAR antagonists exhibited compromised renal inflammatory changes [51,52].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [51] L Moussa, 2007, Protease-activated receptor-2 augments experimental crescentic glomerulonephritis, Am J Pathol source
Not checked in the free run.
- cites [52] SH Slofstra, 2007, Protease-activated receptor-4 inhibition protects from multiorgan failure in a murine model of systemic inflammation, Blood source
Not checked in the free run.
- Interpretationreasoning
There is a bona fide, kidney-specific role of IL-17 in immunity to candidiasis.
“Taken together, these results argue that there is a bona fide, kidney-specific role of IL-17 in immunity to candidiasis.”
Quote in the paperSubstantial claim - Premisecitation
C/EBPβ-/- mice are susceptible to systemic candidiasis.
“C/EBPβ-/- mice are susceptible to systemic candidiasis [48,49].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [48] I Screpanti, 1995, Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice, EMBO J source
Not checked in the free run.
- cites [49] MR Simpson-Abelson, 2015, C/EBPbeta Promotes Immunity to Oral Candidiasis through Regulation of beta-Defensins, PLoS One source
Not checked in the free run.
- Premisecitation
TNFα is required for protection against disseminated candidiasis.
“TNFα is required for protection against disseminated candidiasis [50]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] H Park, 2014, Different tumor necrosis factor alpha antagonists have different effects on host susceptibility to disseminated and oropharyngeal candidiasis in mice, Virulence source
Not checked in the free run.
- May combine two claims. 21
- Classified as probably not a substantial claim. 27
May combine two claims.
Findingown data90% of untreated IL-17RA-/- mice succumbed to infection by day 5 p.i., while mortality was delayed with bradykinin treatment.
“As shown, 90% of the untreated IL-17RA-/- mice succumbed to infection by day 5 p.i., while mortality in IL-17RA-/- mice was delayed with bradykinin treatment (Fig 3A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn C. albicans-infected WT mice, treatment with bradykinin alone but not FLC alone increased survival compared to untreated mice.
“mice treated with bradykinin alone but not FLC demonstrated increased survival compared to untreated mice (Fig 7B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOverexpression of Klk1 had very little impact on renal inflammatory gene expression or fungal load.
“However, we found that overexpression of Klk1 had very little impact on renal inflammatory gene expression or fungal load (Fig 2E and S2D Fig).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBradykinin did not induce IL-6, TNFα, or nitrite in BMDMs in vitro.
“Bradykinin induced IL-6 in RTECs (Fig 5D), but did not induce IL-6, TNFα or nitrite in BMDMs (Fig 5E and 5F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIncreased IL-17 from Ad-IL-17 was not associated with systemic inflammation, as serum TNFα and IL-1β were undetectable.
“This increased level of IL-17 was not associated with systemic inflammation, as serum TNFα and IL-1β levels were undetectable.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataExpression of Bax in kidney-resident cells was comparable between groups, while Bcl-xL expression increased after bradykinin treatment.
“Although expression of Bax (a pro-apoptotic gene) in kidney-resident cells was comparable between the groups, there was an increase in expression of Bcl-xL (an anti-apoptotic gene) after bradykinin treatment (Fig 6E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataKlk1 expression following Ad-IL-17 was restricted to RTEC, with no staining in glomerular and vascular compartments.
“The expression of Klk1 was restricted to RTEC, as no staining could be detected in the glomerular and vascular compartments of the kidney (Fig 2C).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationKidney resident cells express the IL-17R and are responsive to IL-17.
“We also showed that kidney resident cells express the IL-17R and are responsive to IL-17 [47].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] K Ramani, 2014, An essential role of interleukin-17 receptor signaling in the development of autoimmune glomerulonephritis, J Leukoc Biol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn some bacterial and viral infections, bradykinin enhances vascular permeability to facilitate pathogen spread.
“In some bacterial and viral infections, bradykinin enhances vascular permeability to facilitate pathogen spread [26,27].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [26] H Maeda, 1993, Role of bradykinin in microbial infection: enhancement of septicemia by microbial proteases and kinin, Agents Actions Suppl
Not checked in the free run.
- cites [27] NM Rust, 2012, Bradykinin enhances Sindbis virus infection in human brain microvascular endothelial cells, Virology source
Not checked in the free run.
May combine two claims.
PremisecitationMice infected with a low dose of C. albicans (10^5 cfu) exhibit progressive loss of renal function over ~2 weeks, which more accurately reflects disease progression in humans.
“However, mice infected with a low dose of C. albicans (105 cfu) exhibit progressive loss of renal function over a period of ~2 weeks, which more accurately reflects disease progression in humans [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] RD Leunk, 1979, Physiological and metabolic alterations accompanying systemic candidiasis in mice, Infect Immun source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe IL-17-KKS-axis activated bradykinin receptors, which served to enhance renal anti-C. albicans immunity.
“The IL-17-KKS-axis activated bradykinin receptors, which served to enhance renal anti-C. albicans immunity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe KKS was implicated in IL-17-mediated skin inflammation and an IL-17-dependent model of autoimmunity (EAE).
“Additionally, the KKS was implicated in IL-17-mediated skin inflammation and an IL-17-dependent model of autoimmunity (experimental autoimmune encephaloymyelitis, EAE) [30,31].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [30] J Hwang, 2011, Epidermal ablation of Dlx3 is linked to IL-17-associated skin inflammation, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [31] U Schulze-Topphoff, 2009, Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system, Nat Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe renal protective function of the KKS is mediated through upregulation of tissue repair proteins, inhibition of profibrotic factors, and control of apoptosis.
“The renal protective function of the KKS is mediated through upregulation of tissue repair proteins, inhibition of profibrotic factors, and control of apoptosis [21].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] M Kakoki, 2009, The kallikrein-kinin system in health and in diseases of the kidney, Kidney Int source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAt mucosal surfaces, IL-17 mediates antifungal activity by driving expression of antimicrobial peptides and chemokines that facilitate neutrophil influx.
“At mucosal surfaces, IL-17 mediates antifungal activity by driving the expression of antimicrobial peptides and chemokines that facilitate neutrophil influx [18,19].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [18] HR Conti, 2009, Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis, J Exp Med source
Not checked in the free run.
- cites [19] HR Conti, 2014, Oral-resident natural Th17 cells and gammadelta T cells control opportunistic Candida albicans infections, J Exp Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPolymorphisms in KKS-related genes (ACE, BDKRB2, NOS3, KLK1) are associated with increased risk of acute and chronic renal injury in humans.
“Consistently, polymorphisms in KKS-related genes (ACE, BDKRB2, NOS3, KLK1) are associated with an increased risk of acute and chronic renal injury in humans [22–25].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [22] Y Asakimori, 2001, Endothelial nitric oxide synthase intron 4 polymorphism influences the progression of renal disease, Nephron source
Not checked in the free run.
- cites [23] K Baboolal, 1997, Association of the ACE gene deletion polymorphism and early onset of ESRF in PKD1 ADPKD, Kidney International source
Not checked in the free run.
- cites [24] PN Harden, 1995, Polymorphisms in Angiotensin-Converting-Enzyme Gene and Progression of Iga Nephropathy, Lancet source
Not checked in the free run.
- cites [25] L Jozwiak, 2004, Association of the human bradykinin B2 receptor gene with chronic renal failure, Mol Diagn source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCandida hyphae invade and injure the kidney in 30-40% of adults and 50% of neonates, leading to irreversible damage and fatal renal failure.
“However, in 30–40% adults and 50% neonates, Candida hyphae invade and injure the kidney, leading to irreversible damage and fatal renal failure [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] MA Pfaller, 2007, Epidemiology of invasive candidiasis: a persistent public health problem, Clin Microbiol Rev source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKlk1 plays a critical role in renal function and pathology.
“Klk1 in particular plays a critical role in renal function and pathology [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] P Hillmeister, 2012, The Kallikrein-Kinin system, Acta Physiol (Oxf) source
Not checked in the free run.
May combine two claims.
PremisecitationIL-17RA-/-, IL-17RC-/-, RORγt-/- and IL-17A-/- mice are all susceptible to systemic C. albicans infection.
“IL-17RA-/-, IL-17RC-/-, RORγt-/- and IL-17A-/- mice are all susceptible to systemic C. albicans infection [14–17].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- cites [15] E Bar, 2014, IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells, Immunity source
Not checked in the free run.
- cites [16] FL van de Veerdonk, 2010, Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure, Shock source
Not checked in the free run.
- cites [17] AW Ho, 2010, IL-17RC: a partner in IL-17 signaling and beyond, Semin Immunopathol source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationKlk cleave kininogens to generate kinin peptides bradykinin and kallidin.
“Klk cleave kininogens to generate kinin peptides, known as bradykinin and kallidin.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] P Hillmeister, 2012, The Kallikrein-Kinin system, Acta Physiol (Oxf) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStudies in animal models implicate the KKS in regulating inflammation, tissue repair and homeostasis during kidney injury.
“In addition, studies in animal models implicate the KKS in regulating inflammation, tissue repair and homeostasis during kidney injury [21].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] M Kakoki, 2009, The kallikrein-kinin system in health and in diseases of the kidney, Kidney Int source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies have described an anti-apoptotic function of bradykinin in kidney injury.
“Previous studies have described an anti-apoptotic function of bradykinin in kidney injury [41,42].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [41] M Kakoki, 2007, Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [42] H Fan, 2006, Susceptibility to metanephric apoptosis in bradykinin B2 receptor null mice via the p53-Bax pathway, Am J Physiol Renal Physiol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe classic IL-17 gene signature includes neutrophil-related genes and antimicrobial peptides such as CXC chemokines, defensins, calprotectin, and lipocalin 2.
“The classic IL-17 gene signature includes neutrophil-related genes and antimicrobial peptides (AMPs), such as CXC chemokines (Cxcl1,2,5), defensins (Defb3), calprotectin (S100a8) and lipocalin 2 (Lcn2) [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] HR Conti, 2009, Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis, J Exp Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA previous study suggested Klk1 may induce inflammatory cytokines in human RTECs in vitro.
“A previous study suggested that Klk1 may induce inflammatory cytokines in human RTECs, at least in vitro [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] WH Yiu, 2014, Tissue kallikrein mediates pro-inflammatory pathways and activation of protease-activated receptor-4 in proximal tubular epithelial cells, PLoS One source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationConsiderable data have implicated IL-17 in immunity against disseminated candidiasis.
“In recent years, considerable data have implicated IL-17 in immunity against disseminated candidiasis [14–16].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [14] W Huang, 2004, Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice, J Infect Dis source
Not checked in the free run.
- cites [15] E Bar, 2014, IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells, Immunity source
Not checked in the free run.
- cites [16] FL van de Veerdonk, 2010, Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure, Shock source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPrevious studies have shown that neutrophils and monocytes/macrophages mediate fungal clearance in candidiasis.
“Previous studies have shown that neutrophils and monocytes/macrophages mediate fungal clearance in candidiasis [39,40].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [39] MS Lionakis, 2013, CX3CR1-dependent renal macrophage survival promotes Candida control and host survival, J Clin Invest source
Not checked in the free run.
- cites [40] TS Plantinga, 2010, Genetic variation of innate immune genes in HIV-infected african patients with or without oropharyngeal candidiasis, J Acquir Immune Defic Syndr source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKlk1 protects the kidney against acute and chronic disorders in sterile inflammation.
“Klk1 protects the kidney against acute and chronic disorders in sterile inflammation, but has not been linked to candidiasis or IL-17 signaling.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationKlk1 mediates cleavage of kininogens to generate bradykinin, which signals through Bdkrb1 and Bdkrb2.
“Klk1 mediates cleavage of kininogens to generate bradykinin, which signals through Bdkrb1 and Bdkrb2 (Fig 1C) [21].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] M Kakoki, 2009, The kallikrein-kinin system in health and in diseases of the kidney, Kidney Int source
Not checked in the free run.
May combine two claims.
Interpretationown dataKlk1 enhances anti-C. albicans immunity in the kidney in an IL-17-dependent manner, but is not responsible for inducing inflammatory gene expression.
“Overall, these data indicate that Klk1 enhances anti-C. albicans immunity in the kidney in an IL-17-dependent manner, but is not responsible for inducing inflammatory gene expression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDisseminated candidiasis typically impacts individuals with no known underlying immune defects.
“Disseminated candidiasis typically impacts individuals with no known underlying immune defects [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] GD Brown, 2012, Hidden killers: human fungal infections, Sci Transl Med source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationActivation of bradykinin receptors protects the kidney from end-stage renal damage by inducing tissue-protective growth factors and matrix-degrading enzymes.
“Activation of bradykinin receptors protects the kidney from end-stage renal damage by inducing tissue-protective growth factors and matrix-degrading enzymes [21].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] M Kakoki, 2009, The kallikrein-kinin system in health and in diseases of the kidney, Kidney Int source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRTEC are the major producers of Klk1 in chronic kidney diseases.
“These results agree with previous reports indicating that RTEC are the major producers of Klk1 in chronic kidney diseases [34,35].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] C Orfila, 1993, Renal immunolocalization of kallikrein in cisplatin nephrotoxicity in rats, Histochem J source
Not checked in the free run.
- cites [35] C Orfila, 1993, Immunolocalization of renal kallikrein-like substance in rat urinary bladder, Histochem J source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationC. albicans can regulate survival of kidney-resident macrophages via Caspase-3.
“C. albicans can regulate survival of kidney-resident macrophages via Caspase-3 [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] MS Lionakis, 2013, CX3CR1-dependent renal macrophage survival promotes Candida control and host survival, J Clin Invest source
Not checked in the free run.
May combine two claims.
Interpretationown dataUntreated WT mice had a modestly increased survival benefit compared to bradykinin-treated IL-17RA-/- mice, suggesting a Bdkrb-independent pathway may also occur in candidiasis.
“Additionally, untreated WT mice had a modestly increased survival benefit compared to bradykinin treated IL-17RA-/- mice, suggesting that there may also be a Bdkrb-independent pathway occurring in candidiasis.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataBradykinin prevents C. albicans-mediated renal damage and preserves renal function during disseminated candidiasis.
“Collectively, these results indicate that bradykinin prevents C. albicans-mediated renal damage and preserves renal function during disseminated candidiasis.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataData are combined from 3 independent experiments.
“Data are combined from 3 independent experiments.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMost documented IL-17R signaling occurs in non-hematopoietic cells, particularly cells of epithelial and mesenchymal origin.
“most documented IL-17R signaling occurs in non-hematopoietic cells, particularly cells of epithelial and mesenchymal origin [44,45].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKlk1 cleaves kininogens to form bradykinin (the bradykinin-dependent pathway).
“Klk1 cleaves kininogens to form bradykinin, a process known as the bradykinin-dependent pathway [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] P Hillmeister, 2012, The Kallikrein-Kinin system, Acta Physiol (Oxf) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAn antibody targeting IL-17 (secukinumab) was approved in 2016 to treat moderate-severe plaque psoriasis.
“An Ab targeting IL-17 (secukinumab) was approved in 2016 to treat moderate-severe plaque psoriasis [54].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] RG Langley, 2014, Secukinumab in plaque psoriasis—results of two phase 3 trials, N Engl J Med source
Not checked in the free run.
May combine two claims.
PremisecitationKlk1-mediated activation of PAR4 induces cytokine production and prevents apoptosis in RTEC (the bradykinin-independent pathway).
“Klk1-mediated activation of PAR4 induces cytokine production and prevents apoptosis in RTEC, known as the bradykinin-independent pathway [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] WH Yiu, 2014, Tissue kallikrein mediates pro-inflammatory pathways and activation of protease-activated receptor-4 in proximal tubular epithelial cells, PLoS One source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAntibodies against IL-17/IL-17RA are in clinical trials for other autoimmune conditions.
“Abs against IL-17/IL-17RA are in clinical trials for other autoimmune conditions [55].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] P Miossec, 2012, Targeting IL-17 and TH17 cells in chronic inflammation, Nat Rev Drug Discov source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAnimal protocols were approved by the University of Pittsburgh IACUC (Protocol # 14094427) and adhered to NIH guidelines.
“Animal protocols were approved by the University of Pittsburgh IACUC (Protocol # 14094427), and adhered to the guidelines in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningDifferent cell types interpret IL-17 signals differently, with non-identical patterns of gene expression depending on setting.
“different cell types “interpret” IL-17 signals differently, with non-identical patterns of gene expression depending on setting.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBradykinin has been shown to modulate glomerular function by regulating podocyte permeability, an effect independent of its renal tissue protective function.
“bradykinin has been shown to modulate glomerular function by regulating podocyte permeability [53], an effect independent of its renal tissue protective function.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] M Dey, 2010, Bradykinin decreases podocyte permeability through ADAM17-dependent epidermal growth factor receptor activation and zonula occludens-1 rearrangement, J Pharmacol Exp Ther source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were performed a minimum of twice to ensure reproducibility.
“All experiments were performed a minimum of twice to ensure reproducibility.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Drugs targeting the Kallikrein-Kinin System are approved clinically.
“Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.”
The paper relies on this without support.
Bradykinin signals through two receptors, with Bdkrb2 constitutively expressed and Bdkrb1 inducible upon inflammatory signals.
“Bradykinin signals through two receptors; bradykinin receptor β2 (Bdkrb2) is constitutively expressed, whereas Bdkrb1 is inducible upon inflammatory signals.”
The paper relies on this without support.
There is an unmet clinical need to reduce the dosage of current antifungal drugs to overcome drug resistance and toxicity.
“There is an unmet clinical need to reduce the dosage of current antifungal drugs to overcome the problem of drug resistance and toxicity.”
The paper relies on this without support.
How IL-17 regulates immunity within the kidney is unclear.
“it is unclear how IL-17 regulates immunity within the kidney, the most heavily colonized organ during blood-borne C. albicans infection.”
The paper relies on this without support.
The kidney is the most heavily colonized organ during blood-borne C. albicans infection.
“the most heavily colonized organ during blood-borne C. albicans infection.”
The paper relies on this without support.
Disseminated infection typically occurs in individuals with no known defects in IL-17 signaling pathways.
“disseminated infection typically occurs in individuals with no known defects in IL-17 signaling pathways.”
The paper relies on this without support.
Bradykinin therapy has potential side effects.
“Given the potential side effects in bradykinin therapy”
The paper relies on this without support.
Anti-IL-17 therapy may compromise IL-17-driven antifungal immunity.
“One obvious concern with anti-IL-17 therapy is compromising IL-17-driven antifungal immunity.”
The paper relies on this without support.
Patients on secukinumab may have a higher risk of developing disseminated candidiasis in the face of predisposing factors.
“patients on this medication may have a higher risk of developing disseminated candidiasis in the face of predisposing factors, such as an indwelling catheter, abdominal surgery or long-term antibiotic use.”
The paper relies on this without support.
Amphotericin B has intrinsic renal toxicity.
“amphotericin B due its intrinsic renal toxicity.”
The paper relies on this without support.
ACE inhibitors increase the levels of bradykinin.
“ACE inhibitors, known to increase the levels of bradykinin”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IL-17 is protective when the kidney is injured by mechanical obstruction or systemic Candida albicans infection.
“IL-17 is protective when the kidney is injured by mechanical obstruction or systemic Candida albicans infection”
From The IL-17 Family of Cytokines in Health and Disease (2019) · cites this paper as Ramani et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Fig 7 significance inequalities conflict with the paper's notation
MinorFig 7 assigns three and four stars to P values *greater than* 0.001 and 0.0001, respectively. Fig 4 defines those same star levels using P values *less than* those thresholds.
“p<0.05 (*), p>0.001 (***), p>0.0001 (****).”
“P <0.05 (*), <0.01 (**). <0.001 (***), <0.0001 (****). ns, not significant.”
Fluconazole dose timing differs between the figure and methods
MinorThe Fig 7 legend says the second fluconazole dose was given 24 hours after infection, while the Methods say it was given at 26 hours.
“two doses of FLC only (5 mg/kg at 2 and 24 h p.i.)”
“mice were treated with 5, 10, 20 and 40 mg/kg body weight FLC by oral gavage at 2 h and 26 h post infection.”
Cites
Hidden Killers: Human Fungal Infections
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Landivar, M., Tohma, K., Pilewski, K. A., Ford-Siltz, L. A., Kendra, J. A., Gao, Y. S., & Parra, G. I. (2025) · Journal of Virology · doi:10.1128/jvi.00652-25 · Cited by 4 · see citing works
Duda, K. M., Gehring, M., & Wedi, B. (2025) · European Journal of Immunology · doi:10.1002/eji.70010 · Cited by 3 · see citing works
Chimeric PRR T-cell-engager targeting cell surface β-1,3-glucan for invasive candidiasis
Sun, Y., Guo, S. Y., Wang, S. Q., Li, R. T., Qiu, X. R., Dong, X. C., Liu, S., Shen, H., & An, M. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013508 · Cited by 1 · see citing works
Tryptase-like proteases: A novel perspective for fibrosis
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Tissue-type plasminogen activator protects against kidney damage in invasive fungal infection
Choi, W., Peroumal, D., McLaughlin, C. T., Shiomitsu, K. P., Moschetta, G. A., Biswas, K., Kumariduraivan, D., Dicesare, E., & Biswas, P. S. (2026) · The Journal of Experimental Medicine · doi:10.1084/jem.20260530 · Cited by 1 · see citing works
Self-citationBibliometric analysis on the structure and function of IL17
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From confrontation to co-adaptation: the dynamic dialogue of Candida albicans and macrophages
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- Authors
- Ramani, K., Garg, A. V., Jawale, C. V., Conti, H. R., Whibley, N., Jackson, E. K., Shiva, S. S., Horne, W., Kolls, J. K., Gaffen, S. L., & Biswas, P. S.
- Affiliations
- University of Pittsburgh (US)
- University of Toledo (US)
- Children's Hospital of Pittsburgh (US)
- Corresponding author
- Biswas, Partha S.
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-11-04
- Volume
- 12
- Issue
- 11
- Pages
- e1005952
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC5096720
- OpenAlex
- W2548846857
- Semantic Scholar
- a9303a03499adda76dbdb1569878d2c03515194e
- Cited by
- 43
- References
- 61
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 4
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK104680)
- National Institute of Allergy and Infectious Diseases (AI107825)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- kallikrein-kinin system, IL-17, Candida albicans, systemic candidiasis, pyelonephritis, renal protection, bradykinin, KLK1, IL-17RA, renal cell apoptosis, antifungal resistance, nosocomial fungal infections
- MeSH terms
- Animals, Candidiasis, Disease Models, Animal, Flow Cytometry, Immunohistochemistry, Kidney Diseases, Mice, Inbred C57BL, Blotting, Western, Kallikrein-Kinin System, Interleukin-17, Oligonucleotide Array Sequence Analysis, Mice, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
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