Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals

Marques, Catarina; Mega, Cristina; Gonçalves, Andreia; Rodrigues-Santos, Paulo; Teixeira-Lemos, Edite; Teixeira, Frederico; Fontes-Ribeiro, Carlos; Reis, Flávio; Fernandes, Rosa

doi:10.1155/2014/538737

Cited by 126Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesAcute Kidney Injury Research

Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals

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Marques, Catarina, Mega, Cristina, Gonçalves, Andreia, Rodrigues-Santos, Paulo, Teixeira-Lemos, Edite, Teixeira, Frederico, Fontes-Ribeiro, Carlos, Reis, Flávio +1 more·2014·Mediators of Inflammation

DOI 10.1155/2014/538737PMC PMC4000968

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Abstract

This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and bloodHbA1clevels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1β, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia andHbA1c(by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1βand TNF-αlevels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.

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GLP-1-based therapies show anti-inflammatory effects on the liver, vascular system including aorta and vein endothelial cells, brain, kidney, lung, testis, and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues.
“emerging data suggest that GLP-1-based therapies also showed anti-inflammatory effects on the liver, vascular system including aorta and vein endothelial cells, brain, kidney, lung, testis, and skin by reducing the production of inflammatory cytokines and infiltration of immune cells in the tissues [17, 21–25].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [25]
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Sitagliptin (10 mg/kg/day) treatment decreased the expression of proinflammatory cytokine genes IL-1β and TNF-α in kidney of diabetic ZDF rat.
“Sitagliptin (10 mg/kg/day) treatment decreased the expression of proinflammatory cytokine genes IL-1β and TNF-α in kidney of diabetic ZDF rat [25].”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [25]
The Animal Model section reports sitagliptin at 10 mg/kg/day in diabetic ZDF rats. Results §3.4 reports a significant reduction in kidney TNF-α mRNA, but only a nonsignificant trend toward reduced IL-1β mRNA. The claim does not preserve that uncertainty for IL-1β. (LLM, conf=0.88)
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Method
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Background
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Background
(2 R )-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin- 7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
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BackgroundResult
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus
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BackgroundResult
Diabetic Nephropathy: Mechanisms of Renal Disease Progression
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Background
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Background
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Background
Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis
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“It has been previously described that activation of incretin receptors in pancreatic𝛽-cells promotes resistance to apoptosis through the activation of several pathways leading to inhibition of caspase-3, by increasing expression of Bcl2 and decreasing expression of BAX [70, 71].”
BackgroundInfluential
The Pro-Apoptotic Proteins, Bid and Bax, Cause a Limited Permeabilization of the Mitochondrial Outer Membrane That Is Enhanced by Cytosol
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“…Teixeira-Lemos,1,2 Frederico Teixeira,1 Carlos Fontes-Ribeiro,1 Flávio Reis,1 and Rosa Fernandes1,6 1 Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba,…”
Background
The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential
Fujita, H., Morii, T., Fujishima, H., Sato, T., Shimizu, T., Hosoba, M., Tsukiyama, K., Narita, T., Takahashi, T., Drucker, D. J., et al. (2014) · Kidney International · doi:10.1038/ki.2013.427 · Cited by 336 · cited 1× · see citing works
“In addition, we found reduced expression of GLP-1R in the diabetic rats, which was restored in the sitagliptin-treated rats, suggesting a role of GLP-1R signaling in the amelioration of nephropathy, according to other reports [54].”
Result
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Furuta, T., Saito, T., Ootaka, T., Soma, J., Obara, K., Abe, K., & Yoshinaga, K. (1993) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(12)80393-3 · Cited by 324 · cited 1× · see citing works
“In fact, there are reports of infiltration of mononuclear cells in the kidney of patients with DN [63], showing that interstitial inflammatory cells infiltrates are associated with progression of renal injuries in DN [64, 65].”
Background
Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes.
Vestra, M. D., Mussap, M., Gallina, P., Bruseghin, M., Cernigoi, A., Saller, A., Plebani, M., & Fioretto, P. (2005) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004110961 · Cited by 316 · cited 1× · see citing works
“Accumulating evidences point to a critical role of inflammation and proinflammatory cytokines in the development and progression of DN [10, 11].”
Background
Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients
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Background
Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulation of Pancreatic β-Cell Survival Is Dependent upon Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (PKB) Signaling, Inactivation of the Forkhead Transcription Factor Foxo1, and Down-regulation of bax Expression
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GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases
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DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients With Coronary Artery Disease
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Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats
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“However, until now, few studies have addressed the putative beneficial impact of these agents, including sitagliptin, on DN [33–35].”
Background
Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy.
Mezzano, S., Droguett, A., Burgos, M. E., Ardiles, L., Flores, C., Aros, C., Caorsi, I., Vío, C. P., Ruíz-Ortega, M., & Egido, J. (2003) · Kidney international. Supplement · doi:10.1046/j.1523-1755.64.s86.12.x · Cited by 204 · see citing works
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BackgroundResult
Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin, Improves Endothelial Dysfunction in Association With Its Anti-Inflammatory Effects in Patients With Coronary Artery Disease and Uncontrolled Diabetes
Matsubara, J., Sugiyama, S., Akiyama, E., Iwashita, S., Kurokawa, H., Ohba, K., Maeda, H., Fujisue, K., Yamamoto, E., Kaikita, K., et al. (2013) · Circulation Journal · doi:10.1253/circj.cj-12-1168 · Cited by 200 · cited 1× · see citing works
“Several reports have suggested that sitagliptin, a DPPIV inhibitor, confers cytoprotective effects on several tissues, such as heart, kidney, pancreas, and retina [32, 33, 35, 47, 48].”
Background
DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials
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Background
Effects of Sitagliptin Treatment on Dysmetabolism, Inflammation, and Oxidative Stress in an Animal Model of Type 2 Diabetes (ZDF Rat)
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“In conclusion, sitagliptin might be viewed as a promising preventive renoprotective therapeutic strategy against the development and/or progression of diabetic nephropathy.”
BackgroundSelf-citation
Pathogenic perspectives for the role of inflammation in diabetic nephropathy
Rivero, A., Fernández, C. M., Muros, M., Garcı́a, J. G., Herrera, H., & Navarro‐González, J. F. (2009) · Clinical Science · doi:10.1042/cs20080394 · Cited by 190 · see citing works
GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a β-Arrestin 1-mediated ERK1/2 Activation in Pancreatic β-Cells
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“The proinflammatory transcription factor NF-κB was also detected mainly in tubular cells of human and rat kidney, with T2DM and overt nephropathy [67].”
Background
Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice
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“In addition, it was reported that sitagliptin decreases local inflammation in other tissues, such as the adipose tissue and pancreatic islet of obese mice [61].”
Background
High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism.
Kang, B. P. S., Frencher, S. K., Reddy, V., Kessler, A., Malhotra, A., & Meggs, L. (2003) · AJP - Renal Physiology · doi:10.1152/ajprenal.00137.2002 · Cited by 162 · see citing works
Diabetic Nephropathy Amelioration by a Low-Dose Sitagliptin in an Animal Model of Type 2 Diabetes (Zucker Diabetic Fatty Rat)
Mega, C., de Lemos, E. T., Vala, H., Fernandes, R., Oliveira, J., Mascarenhas-Melo, F., Teixeira, F., & Reis, F. (2011) · International Journal of Experimental Diabetes Research · doi:10.1155/2011/162092 · Cited by 161 · cited 4× · see citing works
“Our group has recently shown that sitagliptin corrected the glycaemic dysmetabolism, hypertriglyceridaemia, and inflammation, reduced the severity of histopathological pancreatic lesions, and prevented kidney lesions [35, 44].”
BackgroundMethodInfluentialSelf-citation
Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway
Liu, J., Yin, F., Guo, L., Deng, X., & Hu, Y. (2009) · Acta Pharmacologica Sinica · doi:10.1038/aps.2008.25 · Cited by 140 · cited 1× · see citing works
“In fact, it was found that GLP-1 upregulates Bcl-2 and inhibits BAX expression in cholangiocytes [72], neuronal cells [73, 74], and endothelial cells [75].”
Background
The unique properties of dipeptidyl-peptidase IV (DPP IV / CD26) and the therapeutic potential of DPP IV inhibitors.
Augustyns, K., Bal, G., Thonus, G., Belyaev, A., Zhang, X.-M., Bollaert, W., Lambeir, A., Durinx, C., Goossens, F., & Haemers, A. (1999) · Current Medicinal Chemistry · doi:10.1002/chin.199929294 · Cited by 137
The role of reactive oxygen species in apoptosis of the diabetic kidney
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“In the present study, a proapoptotic state seems to be favored in the kidney of diabetic ZDF rats, which can lead to loss of renal cells and consequent renal function loss [15, 16].”
Background
Taurine Prevents Apoptosis Induced by High Ambient Glucose in Human Tubule Renal Cells
Verzola, D., Bertolotto, M. B., Villaggio, B., Ottonello, L. C., Dallegri, F., Frumento, G., Berruti, V., Gandolfo, M. T., Garibotto, G., & Deferrari, G. (2002) · Journal of Investigative Medicine · doi:10.1136/jim-50-06-04 · Cited by 116 · cited 15× · see citing works
“It has been previously described that activation of incretin receptors in pancreatic𝛽-cells promotes resistance to apoptosis through the activation of several pathways leading to inhibition of caspase-3, by increasing expression of Bcl2 and decreasing expression of BAX [70, 71].”
BackgroundInfluential
Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes.
Vaghasiya, J., Sheth, N., Bhalodia, Y., & Manek, R. (2011) · Regulatory Peptides · doi:10.1016/j.regpep.2010.08.007 · Cited by 113 · cited 1× · see citing works
“Several reports have suggested that sitagliptin, a DPPIV inhibitor, confers cytoprotective effects on several tissues, such as heart, kidney, pancreas, and retina [32, 33, 35, 47, 48].”
Background
Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin‐resistant rats
Apaijai, N., Pintana, H., Chattipakorn, S., & Chattipakorn, N. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12176 · Cited by 110 · see citing works
Diabetes, Inflammation, Proinflammatory Cytokines, and Diabetic Nephropathy
Navarro‐González, J. F., & Fernández, C. M. (2006) · The Scientific World JOURNAL · doi:10.1100/tsw.2006.179 · Cited by 109 · see citing works
Sitagliptin Reduces Cardiac Apoptosis, Hypertrophy and Fibrosis Primarily by Insulin-Dependent Mechanisms in Experimental type-II Diabetes. Potential Roles of GLP-1 Isoforms
Picatoste, B., Ramírez, E., Caro‐Vadillo, A., Iborra, C., Egido, J., Tuñón, J., & Lorenzo, Ó. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078330 · Cited by 101 · cited 1× · see citing works
“It was recently suggested that sitagliptin, via GLP1 stabilization, is able to promote cardioprotection in a model of type 2 diabetic by reducing and limiting hyperglycemia and hyperlipidemia, as well as by promotion of survival and antihypertrophic/fibrotic effects on cultured cardiac cells, via GLP-1 and GLP-1(9-36)…”
Background
Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes
Kodera, R., Shikata, K., Takatsuka, T., Oda, K., Miyamoto, S., Kajitani, N., Hirota, D., Ono, T., Usui, H. K., & Makino, H. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.12.049 · Cited by 101 · see citing works
The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
Ninichuk, V., Khandoga, A. G., Segerer, S., Loetscher, P., Schlapbach, A., Révész, L., Feifel, R., Khandoga, A., Krombach, F., Nelson, P. J., et al. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060937 · Cited by 92 · cited 1× · see citing works
“In fact, there are reports of infiltration of mononuclear cells in the kidney of patients with DN [63], showing that interstitial inflammatory cells infiltrates are associated with progression of renal injuries in DN [64, 65].”
Background
Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood–retinal barrier in a type 2 diabetes animal model
Gonçalves, A., Leal, E. C., Paiva, A. A., Teixeira‐Lemos, E., Teixeira, F. J., Ribeiro, C., Reis, F., Ambrósio, A. F., & Fernandes, R. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01548.x · Cited by 90 · see citing works
Self-citation
Interrelationship of dipeptidyl peptidase IV (DPP4) with the development of diabetes, dyslipidaemia and nephropathy: a streptozotocin-induced model using wild-type and DPP4-deficient rats.
Kirino, Y., Sato, Y., Kamimoto, T., Kawazoe, K., Minakuchi, K., & Nakahori, Y. (2009) · Journal of Endocrinology · doi:10.1677/joe-08-0424 · Cited by 88 · cited 1× · see citing works
“Accordingly to our results, it was reported in a streptozotocin (STZ-) induced diabetic model that enhanced expression of Dpp-IV mRNA in the kidney tissue is correlated with increased circulatingDPP-IV enzyme activity, althoughDPPIV activity in the tissue was found to be significantly reduced after STZ treatment [50].”
Background
Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions.
Yozai, K., Shikata, K., Sasaki, M., Tone, A., Ohga, S., Usui, H., Okada, S., Wada, J., Nagase, R., Ogawa, D., et al. (2005) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004111011 · Cited by 85 · cited 2× · see citing works
“Previous works have shown that the decrease in inflammation promotes an amelioration of diabetic nephropathy [35–37, 60].”
Background
Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells
Pala, L., Mannucci, E., Pezzatini, A., Ciani, S., Sardi, J., Raimondi, L., Ognibene, A., Cappadona, A., Vannelli, B., & Rotella, C. M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.08.111 · Cited by 76 · cited 2× · see citing works
“In fact, there are also some reports suggesting that microvascular endothelial cells are the main sources of endogenous DPP-IV [53] and in vitro studies showed that both Dpp-IV mRNA expression and DPP-IV activity were enhanced by exposure of human glomerular endothelial cells to high glucose [51].”
BackgroundResult
Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries
Matheeussen, V., Baerts, L., Meyer, G. D. D., Keulenaer, G. D., der Veken, P. V., Augustyns, K., Dubois, V., Scharpe, S., & Meester, I. D. (2011) · Biological chemistry · doi:10.1515/bc.2011.002 · Cited by 76 · cited 1× · see citing works
“In fact, there are also some reports suggesting that microvascular endothelial cells are the main sources of endogenous DPP-IV [53] and in vitro studies showed that both Dpp-IV mRNA expression and DPP-IV activity were enhanced by exposure of human glomerular endothelial cells to high glucose [51].”
Background
Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis
Marzioni, M., Alpini, G., Saccomanno, S., Candelaresi, C., Venter, J., Rychlicki, C., Fava, G., Francis, H., Trozzi, L., & Benedetti, A. (2009) · Gut · doi:10.1136/gut.2008.150870 · Cited by 73 · cited 1× · see citing works
“In fact, it was found that GLP-1 upregulates Bcl-2 and inhibits BAX expression in cholangiocytes [72], neuronal cells [73, 74], and endothelial cells [75].”
Background
Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide (1-42).
Qin, Z., Sun, Z.-W., Huang, J., Hu, Y.-H., Wu, Z.-R., & Mei, B. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.08.047 · Cited by 70 · see citing works
New paradigms in cell death in human diabetic nephropathy.
Sánchez-Niño, M., Benito-Martin, A., & Ortiz, A. (2010) · Kidney International · doi:10.1038/ki.2010.270 · Cited by 69 · see citing works
Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function
Nelson, C., Karschimkus, C. S., Dragicevic, G., Packham, D., Wilson, A., O'Neal, D. N., Becker, G. J., Best, J. D., & Jenkins, A. J. (2005) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfi067 · Cited by 63 · cited 1× · see citing works
“Additionally, accumulating evidence also points to a crucial role of the inflammatory process in the development and progression of DN [10–12].”
Background
Anti-apoptotic Action of Exendin-4 in INS-1 Beta Cells: Comparative Protein Pattern Analysis of Isolated Mitochondria
Tews, D., Lehr, S., Hartwig, S., Osmers, A., Passlack, W., & Eckel, J. (2008) · Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme · doi:10.1055/s-0028-1105911 · Cited by 57 · cited 1× · see citing works
“In addition, it was shown that GLP-1 enhances Bcl-2 upregulation [76], BAD inactivation [77], and caspase3 activity reduction [78] in pancreatic β cells.”
Background
Attenuation of Renovascular Damage in Zucker Diabetic Fatty Rat by NWT-03, an Egg Protein Hydrolysate with ACE- and DPP4-Inhibitory Activity
Wang, Y., Landheer, S. W., van Gilst, W. H., van Amerongen, A., Hammes, H., Henning, R. H., Deelman, L. E., & Buikema, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046781 · Cited by 53 · cited 1× · see citing works
“Recently, it has been reported that in the kidney of ZDF (fa/fa) rats the expression of vascular cell adhesionmolecule1 increases with concomitant infiltration of white blood cells, as well as enhanced production of inflammatory cytokines, such as TNF-α and IL-1β, leading to renal cells injury [59].”
Background
Pathogenesis of Diabetic Nephropathy
Dijk, C. M. A. V., & Berl, T. (2004) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/b:remd.0000032412.91984.ec · Cited by 52 · cited 1× · see citing works
“requiring dialysis or transplantation [1, 2].”
Glucagon-like peptide-1 (GLP-1) protects vascular endothelial cells against advanced glycation end products (AGEs) – induced apoptosis
Zhan, Y., Sun, H., Chen, H., Zhang, H., Sun, J. M., Zhang, Z., & Cai, D.-H. (2012) · Medical Science Monitor · doi:10.12659/msm.883207 · Cited by 50 · cited 1× · see citing works
“In fact, it was found that GLP-1 upregulates Bcl-2 and inhibits BAX expression in cholangiocytes [72], neuronal cells [73, 74], and endothelial cells [75].”
Background
Prevention of early renal injury by mycophenolate mofetil and its mechanism in experimental diabetes.
Wu, Y.-G., Lin, H., Qi, X.-M., Wu, G.-Z., Qian, H., Zhao, M., Shen, J.-J., & Lin, S.-T. (2006) · International Immunopharmacology · doi:10.1016/j.intimp.2005.09.006 · Cited by 45 · cited 1× · see citing works
“Previous works have shown that the decrease in inflammation promotes an amelioration of diabetic nephropathy [35–37, 60].”
Background
Mechanisms and consequences of hypertriglyceridemia and cellular lipid accumulation in chronic kidney disease and metabolic syndrome.
Lee, H. S. (2011) · PubMed · doi:10.14670/hh-26.1599 · Cited by 39 · see citing works
Sid knocks them out
Rockett, J. (2002) · Genome Biology · doi:10.1186/gb-2002-3-7-reports0034 · Cited by 32 · see citing works
Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats
Tone, A., Shikata, K., Sasaki, M., Ohga, S., Yozai, K., Nishishita, S., Usui, H., Nagase, R., Ogawa, D., Okada, S., et al. (2005) · Diabetologia · doi:10.1007/s00125-005-1945-6 · Cited by 31 · cited 2× · see citing works
“Previous works have shown that the decrease in inflammation promotes an amelioration of diabetic nephropathy [35–37, 60].”
Background
Novel therapies for the management of type 2 diabetes mellitus: Part 2. Addressing the incretin defect in the clinical setting in 2013 (新型2型糖尿病治疗药物：第2部分. 2013年临床上针对肠促胰岛素缺陷的治疗药物)
Grunberger, G. (2013) · Journal of Diabetes · doi:10.1111/1753-0407.12046 · Cited by 8 · see citing works

Flagged first, then by citations

6 of the 80 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

[6]Tanji N Markowitz GS Fu C Expression of advanced glycation end products and their cellular receptor RAGE diabetic nephropathy and nondiabetic renal disease Journal of the American Society of Nephrology 2000 11 9 1656 1666 2-s2.0-0033848466 10966490
[26]Aschner P Kipnes MS Lunceford JK Sanchez M Mickel C Williams-Herman DE Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes Diabetes Care 2006 29 12 2632 2637 2-s2.0-33845472504 17130196
[38]Ohga S Shikata K Yozai K Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation American Journal of Physiology: Renal Physiology 2007 292 4 F1141 F1150 2-s2.0-34147213227 17190910
[40]Janssen U Phillips AO Floege J Rodent models of nephropathy associated with type II diabetes Journal of Nephrology 1999 12 3 159 172 2-s2.0-0032777587 10440513
[68]Guijarro C Egido J Transcription factor-κB (NF-κB) and renal disease Kidney International 2001 59 2 415 424 2-s2.0-0035137324 11168923
[76]Natalicchio A de Stefano F Orlando MR Exendin-4 prevents c-Jun N-terminal protein kinase activation by Tumor Necrosis Factor-α (TNFα) and inhibits TNFα-induced apoptosis in insulin-secreting cells Endocrinology 2010 151 5 2019 2029 2-s2.0-77953148018 20219981

Sorted by citations

Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives.
Bhatti, J. S., Sehrawat, A., Mishra, J., Sidhu, I. S., Navik, U., Khullar, N., Kumar, S., Bhatti, G. K., & Reddy, P. (2022) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2022.03.019 · Cited by 649 · see citing works
Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control
Lee, Y.-S., & Jun, H.-S. (2016) · Mediators of Inflammation · doi:10.1155/2016/3094642 · Cited by 503 · see citing works
“Sitagliptin (10mg/kg/day) treatment decreased the expression of proinflammatory cytokine genes IL-1β and TNF-α in kidney of diabetic ZDF rat [25].”
Background
Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent
Mehdi, S. F., Pusapati, S., Anwar, M. S., Lohana, D., Kumar, P., Nandula, S. A., Nawaz, F. K., Tracey, K., Yang, H., LeRoith, D., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1148209 · Cited by 317 · see citing works
Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling
Oh, Y., & Jun, H.-S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms19010026 · Cited by 217 · see citing works
Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence
Alicic, R. Z., Cox, E. J., Neumiller, J. J., & Tuttle, K. R. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-020-00367-2 · Cited by 193 · see citing works
Diabetic nephropathy: An update on pathogenesis and drug development
Rao, V., Tan, S. H., Candasamy, M., & Bhattamisra, S. K. (2018) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2018.11.054 · Cited by 190 · see citing works
The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications
Avogaro, A., & Fadini, G. P. (2014) · Diabetes Care · doi:10.2337/dc14-0865 · Cited by 152 · see citing works
“Such data indicate protective effects against inflammation and apoptosis in the kidney (88).”
Background
Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity
Abo‐Haded, H. M., Elkablawy, M. A., Al-johani, Z., Al-ahmadi, O., & El‐Agamy, D. S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174295 · Cited by 142 · see citing works
Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes
Teodoro, J. S., Nunes, S., Rolo, A. P., Reis, F., & Palmeira, C. M. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01857 · Cited by 149 · see citing works
Self-citation
Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson’s disease
Badawi, G. A., Fattah, M. A. A. E., Zaki, H. F., & Sayed, M. I. E. (2017) · Inflammopharmacology · doi:10.1007/s10787-017-0331-6 · Cited by 123 · see citing works
The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A “Me Too” or “the Special One” Antidiabetic Class?
Godinho, R., Mega, C., Teixeira‐Lemos, E., Carvalho, E., Teixeira, F. J., Fernandes, R., & Reis, F. (2015) · Journal of Diabetes Research · doi:10.1155/2015/806979 · Cited by 109 · see citing works
“Our group has shown beneficial effects of sitagliptin not only on the pancreas but also on the heart, kidney, and retina in animal models of T1DM and T2DM [116, 252, 255, 256, 258], which are in line with other studies focused on cardiomyopathy, nephropathy, and retinopathy.”
BackgroundResultSelf-citation
Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection
Tomović, K., Lazarević, J., Kocic, G., Deljanin-Ilić, M., Anderluh, M., & Šmelcerović, A. (2018) · Medicinal research reviews (Print) · doi:10.1002/med.21513 · Cited by 84 · see citing works
Diet‐induced rodent models of obesity‐related metabolic disorders—A guide to a translational perspective
Preguiça, I., Alves, A., Nunes, S., Fernandes, R., Gomes, P., Viana, S., & Reis, F. (2020) · Obesity Reviews · doi:10.1111/obr.13081 · Cited by 113 · see citing works
Self-citation
Postprandial renal haemodynamic effect of lixisenatide vs once‐daily insulin‐glulisine in patients with type 2 diabetes on insulin‐glargine: An 8‐week, randomised, open‐label trial
Tonneijck, L., Muskiet, M. H. A., Smits, M. M., Hoekstra, T., Kramer, M. H. H., Danser, A. H. J., Diamant, M., Joles, J. A., & van Raalte, D. H. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12985 · Cited by 62 · see citing works
“After 8 weeks, median (IQR) iGlu dose was 17 (8-29) units/d.”
Background
Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy
Preguiça, I., Alves, A., Nunes, S., Gomes, P., Fernandes, R., Viana, S., & Reis, F. (2020) · Nutrients · doi:10.3390/nu12010250 · Cited by 74 · see citing works
Self-citation
Novel Therapies for Acute Kidney Injury
Chen, H., & Busse, L. W. (2017) · Kidney International Reports · doi:10.1016/j.ekir.2017.06.020 · Cited by 64 · see citing works
Renoprotective Effects of DPP-4 Inhibitors
Kawanami, D., Takashi, Y., Takahashi, H., Motonaga, R., & Tanabe, M. (2021) · Antioxidants · doi:10.3390/antiox10020246 · Cited by 57 · see citing works
“Sitagliptin has been shown to prevent apoptotic cell death in the kidney of ZDF-rats, as indicated by reductions in the BAX/Bcl-2 ratio, Bid protein levels, and numbers of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the kidney sections [98].”
Background
Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy
Jo, C. H., Kim, S., Park, J.-S., & Kim, G.-H. (2018) · Kidney & Blood Pressure Research · doi:10.1159/000490688 · Cited by 51
DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control
Bae, E. J. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0813-x · Cited by 52 · see citing works
“On the other hand, GLP-1-dependent nephroprotective effects have been reported in STZ-induced and genetic diabetic rodent models (Liu et al. 2012; Marques et al. 2014).”
Background
Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats.
Yin, W., Xu, S.-Q., Wang, Z., Liu, H., Peng, L., Fang, Q., Deng, T., Zhang, W.-J., & Lou, J. (2018) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2017.11.076 · Cited by 48 · see citing works
Gemigliptin improves renal function and attenuates podocyte injury in mice with diabetic nephropathy.
Jung, E., Kim, J., Kim, S. H., Kim, S., & Cho, M. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.04.055 · Cited by 46 · see citing works
Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax
Abd-Eldayem, A. M., Makram, S. M., Messiha, B., Abd-Elhafeez, H. H., & Abdel-Reheim, M. A. (2024) · Scientific Reports · doi:10.1038/s41598-024-57300-x · Cited by 43 · see citing works
“…that reported the capability of sitagliptin to improve kidney function and attenuate the histopathological changes in different experimental models such as diabetic nephropathy 114 , ischemia–reperfusion injury 34 , gentamicin nephrotoxicity 115 , and cisplatin-induced nephrotox-icity in mice 116 .”
Background
Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence
Kawanami, D., Matoba, K., Sango, K., & Utsunomiya, K. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17081223 · Cited by 46 · see citing works
“Sitagliptin also has been shown to attenuate glomerulosclerosis and tubulointerstitial fibrosis by decreasing the levels of inflammatory cytokines such as IL-1β and TNF-α as well as cellular apoptosis in the kidney of ZDF rats [40].”
Background
Renoprotective effect of DPP-4 inhibitors against free fatty acid-bound albumin-induced renal proximal tubular cell injury.
Tanaka, Y., Kume, S., Chin-Kanasaki, M., Araki, H., Araki, S., Ugi, S., Sugaya, T., Uzu, T., & Maegawa, H. (2016) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2016.01.109 · Cited by 40
Glucagon‑like peptide‑1 protects mouse podocytes against high glucose‑induced apoptosis, and suppresses reactive oxygen species production and proinflammatory cytokine secretion, through sirtuin 1 activation in�vitro
Shi, J., & Huang, Q. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9085 · Cited by 31 · see citing works
“These results are consistent with those of a previous study, which reported increased TNF-α , IL-1 β and IL-6 levels in the kidneys of diabetic rats (1).”
Nephroprotective effect of Artemisia herba alba aqueous extract in alloxan-induced diabetic rats
Sekiou, O., Boumendjel, M., Taibi, F., Tichati, L., Boumendjel, A., & Messarah, M. (2020) · Journal of Traditional and Complementary Medicine · doi:10.1016/j.jtcme.2020.01.001 · Cited by 38
Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes
Mega, C., Teixeira‐Lemos, E., Fernandes, R., & Reis, F. (2017) · Journal of Diabetes Research · doi:10.1155/2017/5164292 · Cited by 37 · see citing works
“With disease aggravation, glomerulosclerosis and glomerular atrophy become evident (Figure 1(a)), confirming the link between diabetes (hyperglycaemia and hyperlipidaemia) and progressive renal injury [8, 126].”
BackgroundInfluentialSelf-citation
The incretin system ABCs in obesity and diabetes – novel therapeutic strategies for weight loss and beyond
João, A. L., Reis, F., & Fernandes, R. (2016) · Obesity Reviews · doi:10.1111/obr.12421 · Cited by 45 · see citing works
“In fact, antiinflammatory properties of such medications had already been demonstrated in the context of T2DM vascular complications, namely, regarding the diminution of proinflammatory cytokines (46,52,54).”
BackgroundInfluentialSelf-citation
Maackiain Protects the Kidneys of Type 2 Diabetic Rats via Modulating the Nrf2/HO-1 and TLR4/NF-κB/Caspase-3 Pathways
Guo, J.-H., Li, J., Wei, H., & Liang, Z. (2021) · Drug Design, Development and Therapy · doi:10.2147/dddt.s326975 · Cited by 36 · see citing works
Treatment of diabetic kidney disease: current and future targets
Kim, M. K. (2017) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2016.219 · Cited by 36 · see citing works
“Numerous preclinical and clinical studies now support the notion that DPP-4 exerts a renoprotective effect [24,27-38]; the studies are summarized in Table 1.”
Background
Obesity and brain inflammation: a focus on multiple sclerosis
Palavra, F., Almeida, L., Ambrósio, A. F., & Reis, F. (2016) · Obesity Reviews · doi:10.1111/obr.12363 · Cited by 36 · see citing works
Self-citation
Exendin-4 regulates Wnt and NF-κB signaling in lipopolysaccharide-induced human periodontal ligament stem cells to promote osteogenic differentiation
Liu, H., Zheng, J., Zheng, T.-J., & Wang, P. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.105801 · Cited by 40 · see citing works
DA-1229, a dipeptidyl peptidase IV inhibitor, protects against renal injury by preventing podocyte damage in an animal model of progressive renal injury
Lee, J. E., Kim, J. E., Lee, M. H., Song, H., Ghee, J., Kang, Y. S., Min, H., Kim, H. W., Cha, J., Han, J., et al. (2016) · Laboratory Investigation · doi:10.1038/labinvest.2016.34 · Cited by 35 · see citing works
Hinokinin alleviates high fat diet/streptozotocin-induced cardiac injury in mice through modulation in oxidative stress, inflammation and apoptosis
Lu, Q., Zheng, R., Zhu, P., Bian, J., Liu, Z., & Du, J. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111361 · Cited by 35 · see citing works
The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes
Moon, J.-Y., Woo, J. S., Seo, J.-W., Lee, A., Kim, D. J., Kim, Y., Kim, S.-Y., Lee, K. H., Lim, S., Cheng, X. W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150745 · Cited by 34 · see citing works
“GLP-1-independent renoprotective effects have also been reported in streptozotocin-induced and genetic diabetic rodent models [14,15,16].”
Background
Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury
Lim, S. W., Jin, L., Piao, S., Chung, B., & Yang, C.-W. (2015) · Laboratory Investigation · doi:10.1038/labinvest.2015.93 · Cited by 32
Effect of combined therapy of mesenchymal stem cells with GLP-1 receptor agonist, exenatide, on early-onset nephropathy induced in diabetic rats
Habib, H. A., Heeba, G. H., & Khalifa, M. M. A. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173721 · Cited by 33 · see citing works
Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin‐induced nephrotoxicity
Abuelezz, S. A., Hendawy, N., & Gawad, S. A. (2016) · The Journal of pharmacy and pharmacology · doi:10.1111/jphp.12534 · Cited by 31
“Sitagliptin exerts a renoprotective effect against ischaemia– reperfusion injury through attenuating oxidative stress([18]) and also prevents apoptotic cell death in the kidney of type 2 diabetic animals.([19]) Moreover, sitagliptin improves the cardiac mitochondrial dysfunction([17]) and attenuates the brain mitochon…”
BackgroundResult
Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade
Salama, R. M., Nasr, M. M., Abdelhakeem, J. I., Roshdy, O. K., & ElGamal, M. A. (2020) · Drug and Chemical Toxicology · doi:10.1080/01480545.2020.1814319 · Cited by 32 · see citing works
“Similarly, DPP-IV inhibition by sitagliptin resulted in repressed renal inflammatory cascade, as witnessed through reduced TNF-a levels, which might justify the enhanced renal function and alleviation of renal lesions (Marques et al. 2014).”
Background
Mitochondrion-driven nephroprotective mechanisms of novel glucose lowering medications
Afşar, B., Hornum, M., Afşar, R. E., Ertuğlu, L. A., Ortíz, A., Covic, A. C., van Raalte, D. H., Cherney, D. Z. I., & Kanbay, M. (2021) · Mitochondrion · doi:10.1016/j.mito.2021.02.016 · Cited by 28 · see citing works
Dipeptidyl peptidase 4 promotes peritoneal fibrosis and its inhibitions prevent failure of peritoneal dialysis
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Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway
AL-Qabbaa, S. M., Qaboli, S. I., Alshammari, T. K., Alamin, M. A., Alrajeh, H. M., Almuthnabi, L. A., Alotaibi, R. R., Alonazi, A. S., Dayel, A. F. B., Al‐Rasheed, N. M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076532 · Cited by 27 · see citing works
“Therefore, by incr asing the concentration of active GLP-1, s tagliptin may synergistically reduce inflammation in abetic kidneys [44,45].”
Background
Cathepsin D plays a role in endothelial–pericyte interactions during alteration of the blood–retinal barrier in diabetic retinopathy
Monickaraj, F., Mcguire, P., & Das, A. (2017) · The FASEB Journal · doi:10.1096/fj.201700781rr · Cited by 24 · see citing works
Anti-inflammatory drugs as promising cardiovascular treatments
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Novel avenues for treating diabetic nephropathy: new investigational drugs
Lacava, V., Pellicanò, V., Ferrajolo, C., Cernaro, V., Visconti, L., Conti, G., Buemi, M., & Santoro, D. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1293039 · Cited by 24 · see citing works
“Other authors found a decrease in the concentration of inflammatory and pro-fibrotic cytokines in animal models of diabetes treated with sitagliptin [130].”
Background
Effect of Dipeptidyl Peptidase-4 Inhibitors on Plasma Adiponectin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
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The dipeptidyl peptidase 4 inhibitor sitagliptin improves oxidative stress and ameliorates glomerular lesions in a rat model of type 1 diabetes
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Self-citation
Exenatide and Sitagliptin Decrease Interleukin 1β, Matrix Metalloproteinase 9, and Nitric Oxide Synthase 2 Gene Expression But Does Not Reduce Alveolar Bone Loss in Rats With Periodontitis.
Moraes, R. M., Lima, G. M. G., Oliveira, F. E., Brito, A. C. V., Pereira, R. C., Oliveira, L. D., Barros, P. P., Franco, G. C., & Anbinder, A. (2015) · The Journal of Periodontology · doi:10.1902/jop.2015.150278 · Cited by 21 · see citing works
Effects of Incretin-Based Therapies on Diabetic Microvascular Complications
Kang, Y. M., & Jung, C. H. (2017) · Endocrinology and Metabolism · doi:10.3803/enm.2017.32.3.316 · Cited by 16 · see citing works
DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid
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“Furthermore, the treatment of ZDF rats with sitagliptin also ameliorated nitrosative stress, inflammation and apoptosis in retinal cells, and prevented diabetic nephropathy progression through antiinflammatory and anti-apoptotic properties [44–46].”
Background
Sitagliptin's renoprotective effect in a diabetic nephropathy model in rats: The potential role of PI3K/AKT pathway
Mohamed, R. H., Sedky, A. A., Hamam, G. G., Elkhateb, L. A., Kamar, S. A., Adel, S., & Tawfik, S. S. (2021) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12736 · Cited by 19 · see citing works
“SIT prevented the proapoptotic state and the increase in both mRNA and protein levels of proinflammatory cytokines, including TNF-α and others in diabetic kidneys of ZDF rats [50].”
Background
Effect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy
Ren, X.-J., Zhu, R.-F., Liu, G.-H., Xue, F.-P., Wang, Y.-H., Xu, J., Zhang, W., Yu, W.-M., & Li, R. (2019) · Nephrology · doi:10.1111/nep.13641 · Cited by 19 · see citing works
“Marques et al.(22)confirmed that sitagliptin can attenuate the high expression of DPP-4, restore the biological activity of GLP-1, and further reduce proteinuria and pathological damage to the glomeruli and tubulointerstitial area in diabetic rats.”
Background
Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas and Other Glucose-lowering Therapies for Three Acute Outcomes
Gamble, J., Donnan, J. R., Chibrikov, E., Twells, L., Midodzi, W. K., & Majumdar, S. R. (2018) · Scientific Reports · doi:10.1038/s41598-018-33483-y · Cited by 24 · see citing works
Sitagliptin exerts anti-apoptotic effect in nephrotoxicity induced by cisplatin in rats
Abdelrahman, R. S. (2017) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-017-1367-2 · Cited by 17 · see citing works
“These results are correlated with previous studies which reported anti-inflammatory effect of sitagliptin in different organs (Nader et al. 2012; El-Agamy et al. 2016) and, particularly, in the kidney organ (Li et al. 2014; Marques et al. 2014; Shalaby and Malek 2014; Chang et al. 2015).”
BackgroundResultInfluential
Diabetic Cardiomyopathy: Focus on Oxidative Stress, Mitochondrial Dysfunction and Inflammation
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Self-citation
No Difference in Short-term Surgical Outcomes From Semaglutide Treatment for Type 2 Diabetes Mellitus After Cervical Decompression and Fusion
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“17,18 Initially recognized as a type of incretins that promotes insulin secretion and inhibits glucagon secretion, the pleiotropic effects of GLP-1 receptor agonists have been expanded from energy homeostasis to cardiovascular functions and anti-in ﬂ ammatory effects.”
The effects of dipeptidyl peptidase‐4 inhibitors on kidney outcomes
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Sitagliptin Attenuates Endothelial Dysfunction of Zucker Diabetic Fatty Rats: Implication of the Antiperoxynitrite and Autophagy
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Dipeptidyl peptidase-4 inhibition and renoprotection
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Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats.
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Crescent-Like Lesions as an Early Signature of Nephropathy in a Rat Model of Prediabetes Induced by a Hypercaloric Diet
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“Interestingly, a linkage between diabetic glomerulopathy and crescent-like structures has already been pinpointed in Zucker diabetic fatty (ZDF) rats, a genetic T2DM animal model widely used in the preclinical setting as they spontaneously develop insulin resistance and obesity at a young age and progressively develop…”
Self-citation
Immunohistochemical, apoptotic and biochemical changes by dipeptidyl peptidase-4 inhibitor-sitagliptin in type-2 diabetic rats
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Dipeptidyl peptidase-4 inhibitors in progressive kidney disease
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“Recently, a study with similar experimental settings of low-dose sitagliptin administration for 6 weeks in ZDF rat demonstrated that sitagliptin prevented the tubulointerstitial and glomerular lesions [48].”
BackgroundResult
Decreased expression of Glucagon-like peptide-1 receptor and Sodium-glucose co-transporter 2 in patients with proliferative diabetic retinopathy
Chen, H., Zhang, X., Liao, N., Ji, Y., Mi, L., Gan, Y., Su, Y., & Wen, F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1020252 · Cited by 13 · see citing works
Sitagliptin Repositioning in SARS-CoV-2: Effects on ACE-2, CD-26, and Inflammatory Cytokine Storms in the Lung.
Dastan, F., Abedini, A., Shahabi, S., Kiani, A., Saffaei, A., & Zare, A. (2020) · Iranian Journal of Allergy, Asthma and Immunology · doi:10.18502/ijaai.v19i(s1.r1).2849 · Cited by 13
Resistance Exercise Training Attenuates the Loss of Endogenous GLP-1 Receptor in the Hypothalamus of Type 2 Diabetic Rats
Park, S. H., Yoon, J.-H., Seo, D., Kim, T. N., Ko, J., & Han, J. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16050830 · Cited by 13 · see citing works
“Progressive hyperglycemia, a major feature of T2DM, contributes to the dysfunction of several organs, including the central and peripheral systems, eventually leading to diabetic complications [2,3].”
Background
Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner
Kitada, M., Tsuda, S.-I., Konishi, K., Takeda-Watanabe, A., Fujii, M., Kanasaki, K., Nishizawa, M., Nakagawa, A., & Koya, D. (2017) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2017-000391 · Cited by 13 · see citing works
The Effects of Dipeptidyl Peptidase 4 Inhibitors on Renal Function in Patients with Type 2 Diabetes Mellitus
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EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation
Ha, K., Sangartit, W., Jeong, A. R., Lee, E. S., Kim, H.-M., Shim, S., Kukongviriyapan, U., Kim, D.-K., Lee, E. Y., & Chung, C. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2021.1305 · Cited by 12 · see citing works
“Bax/Bcl2 is an indicator of response to the apoptotic signal and subsequent activation [43].”
Background
Incretin-based therapy: a new horizon in diabetes management
Zarei, M., Vaighan, N. S., Farjoo, M. H., Talebi, S., & Zarei, M. (2024) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-024-01479-3 · Cited by 11 · see citing works
“…], which offers DPP-4 as a marker of tubular injury in diseases and DPP-4 inhibitors through attenuating inflammatory cytokines and markers, such as IL-1β, TNF-α, chemoat - tractant protein-1 (MCP1), and high-sensitivity C-reactive protein (hs-CRP) in DKD cases and models [ 170, 174 , 199– 202].”
Sitagliptin ameliorates L-arginine-induced acute pancreatitis via modulating inflammatory cytokines expression and combating oxidative stress
Eltahir, H. M., Elbadawy, H. M., Almikhlafi, M. A., Alalawi, A., Aldhafiri, A. J., Alahmadi, Y., Althagfan, S. S., Albadrani, M., Eweda, S. M., & Abouzied, M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1389670 · Cited by 11
Use of DPP4i reduced odds of clinical deterioration and hyperinflammatory syndrome in COVID-19 patients with type 2 diabetes: Propensity score analysis of a territory-wide cohort in Hong Kong
Wong, C., Lui, D. T., Lui, A. Y. C., Kwok, A. C. Y., Low, M. C. H., Lau, K., Au, I., Xiong, X.-Q., Chung, M., Lau, E., et al. (2021) · Diabetes & Metabolism · doi:10.1016/j.diabet.2021.101307 · Cited by 11
“Moreover, studies have proposed that chronic inflammation characterizing obesity and T2DM may be traced to a common phenomenon: the upregulation of dipeptidyl peptidase 4 (DPP4), or cluster of differentiation 26 (CD26) in immune cell populations among adipocytes [7, 8].”
BackgroundResult
Renoprotective Effects of Incretin‐Based Therapy in Diabetes Mellitus
Yaribeygi, H., Atkin, S. L., Montecucco, F., Jamialahmadi, T., & Sahebkar, A. (2021) · BioMed Research International · doi:10.1155/2021/8163153 · Cited by 13 · see citing works
“Moreover, Marques and coworkers in 2014 demonstrated that sitagliptin therapy attenuated the levels of IL-1β and TNF-α and decreased the inflammatory responses in kidneys in diabetic animals [55].”
Background
Comparative effects of incretin-based therapy on early-onset diabetic nephropathy in rats: Role of TNF-α, TGF-β and c-caspase-3
Habib, H. A., Heeba, G. H., & Khalifa, M. M. A. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119624 · Cited by 14 · see citing works
Exenatide modulates expression of metalloproteinases and their tissue inhibitors in TNF-α stimulated human retinal pigment epithelial cells
Garczorz, W., Gallego-Colón, E., Kosowska, A., Siemianowicz, K., Kłych‐Ratuszny, A., Woźniak, M., Aghdam, M. R. F., Francuz, T., & Dorecka, M. (2018) · Pharmacological Reports · doi:10.1016/j.pharep.2018.10.003 · Cited by 12 · see citing works
Effect of dipeptidyl peptidase‐4 inhibitors on complement activation
Hoffmann-Petersen, I. T., Holt, C. B., Jensen, L., Hage, C., Mellbin, L., Thiel, S., Hansen, T. K., & Østergaard, J. (2020) · Diabetes/Metabolism Research Reviews · doi:10.1002/dmrr.3385 · Cited by 10 · see citing works
“found that low-dose sitagliptin ameliorated glomerular, tubulointerstitial, and vascular lesions in a T2D rat model of diabetic nephropathy.(31) Kodera et al.”
Background
Sphingosine kinase 1–interacting protein is a dual regulator of insulin and incretin secretion
Liu, Y., Harashima, S., Wang, Y., Suzuki, K., Tokumoto, S., Usui, R., Tatsuoka, H., Tanaka, D., Yabe, D., Harada, N., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201801783rr · Cited by 10 · see citing works
The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial
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Involvement of brain natriuretic peptide signaling pathway in the cardioprotective action of sitagliptin
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Incretin-based therapy: renal effects
Korbut, A. I., & Klimontov, V. V. (2016) · Diabetes Mellitus · doi:10.14341/dm7727 · Cited by 13 · see citing works
Nephroprotection by Hypoglycemic Agents: Do We Have Supporting Data?
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“↓IL-1β, ↓TNF-α, ↓Bid protein levels in experimental studies [60] Sitagliptin decreases albuminuria after 6 moths”
New Insights into the Pleiotropic Actions of Dipeptidyl Peptidase-4 Inhibitors Beyond Glycaemic Control
Mangoura, S. A., Ahmed, M. A., & Zaka, A. Z. (2024) · touchREVIEWS in Endocrinology · doi:10.17925/ee.2024.20.2.5 · Cited by 10 · see citing works
“125 The B cell lymphoma-2 (BCL-2) family of proteins has a central role in modulating the intrinsic pathway of apoptosis through controlling mitochondrial permeability.”
Background
Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats
Fard, L. A., Malekinejad, H., Esmaeilzadeh, Z., Jafari, A., Khezri, M., & Ghasemnejad-Berenji, M. (2023) · Journal of environmental science and health. Part C, Toxicology and carcinogenesis · doi:10.1080/26896583.2023.2186683 · Cited by 8 · see citing works
Saxagliptin protects against diabetic nephropathy by inhibiting caspase 3/PARP-1-dependent nephrocyte apoptosis
Xing, X.-W., Guo, S., Liu, Y.-S., Kuang, J., Huang, Z.-W., Wang, X., & Lu, Q. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10422 · Cited by 8 · see citing works
“Similarly, the DPP‐4 inhibitor linagliptin ameliorated DM‐induced kidney damage by inhibiting apoptosis (5).”
Background
High glucose stimulates cell proliferation and Collagen IV production in rat mesangial cells through inhibiting AMPK-KATP signaling
Zhang, B., Shi, Y., Zou, J., Chen, X., Tang, W., Ye, F., & Liu, Z. (2017) · International Urology and Nephrology · doi:10.1007/s11255-017-1654-3 · Cited by 8 · see citing works
DPP4 regulates the inflammatory response in a rat model of febrile seizures
Sun, Q., Zhang, Y.-S., Huang, J., Yu, F., Xu, J., Peng, B., Liu, W.-H., Han, S., Yin, J., & He, X.-H. (2017) · Bio-medical materials and engineering · doi:10.3233/bme-171635 · Cited by 8
Dipeptidyl peptidase IV inhibition delays developmental programming of obesity and metabolic disease in male offspring of obese mothers
Montaniel, K. R., Bucher, M., Phillips, E. A., Li, C., Sullivan, E., Kievit, P., Rugonyi, S., Nathanielsz, P., & Maloyan, A. (2022) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174422000010 · Cited by 7 · see citing works
Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes
Oltulu, Ç., Ersoy, O., Akıncı, M., YAKUT, Z. A. Ç., Daşman, M., & Bakar, E. (2024) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2024.117119 · Cited by 6 · see citing works
Anagliptin prevents apoptosis of human umbilical vein endothelial cells by modulating NOX-4 signaling pathways
Li, Q., Li, J., Liu, Y., Zhang, M., & Chen, C. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.04.187 · Cited by 8 · see citing works
Retinal pigment epithelium-derived extracellular vesicles mediate outer blood retinal barrier disruption in response to AMD-related stress
Martins, B., Boia, R., Correia, D., Ribeiro-Rodrigues, T. M., Ramalho, J., Ambrósio, A. F., Girão, H., & Fernandes, R. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02587-0 · Cited by 5
“Western blot analysis of pRPE cells or isolated EVs was performed as previously described [25].”
Self-citation
Dipeptidyl-Peptidase 4 Inhibitors did not Improve Renal Endpoints in Advanced Diabetic Kidney Disease.
Kornelius, E., Huang, C.-N., Lo, S.-C., Wang, Y.-H., & Yang, Y.-S. (2020) · Endocrine Practice · doi:10.4158/ep-2020-0143 · Cited by 4 · see citing works
Impact of type 1 diabetes mellitus and sitagliptin treatment on the neuropeptide Y system of rat retina
Campos, E. J., Martins, J., Brudzewsky, D., Correia, S., Santiago, A. R., Woldbye, D. P. D., & Ambrósio, A. F. (2018) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.13176 · Cited by 4 · see citing works
“Research carried out using type 2 DM animal models corroborate this effect of sitagliptin in hyperglycaemia.(25,35,36) For type 1 DM, the sitagliptin studies available in patients are not consistent.”
Method
Anti-inflammatory effects of gastric bypass surgery and their association with improvement in metabolic profile
Neff, K., O’Donohoe, P. K., & le Roux, C. W. (2015) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.2015.1054808 · Cited by 4 · see citing works
“For example, in diabetic kidney disease, sitagliptin can reduce the degree of renal inflammation, including the expression of TNF-a, resulting in improved histological outcomes [144].”
Background
Antioxidant and apoptotic activities of sitagliptin against hepatocellular carcinoma: An in vitro study
Alameen, R., Bairam, A., & Al-Haddad, M. (2023) · F1000Research · doi:10.12688/f1000research.139277.1 · Cited by 3
A dipeptidyl peptidase IV inhibitory peptide relieves palmitic acid-induced endoplasmic reticulum stress in HepG2 cells independent of inhibiting dipeptidyl peptidase IV activity
Jin, R., Ren, H., Liao, M., Shang, J., Wang, D., Li, M., & Liu, N. (2021) · Food & Function · doi:10.1039/d1fo02283k · Cited by 3 · see citing works
mTOR in Diabetic Nephropathy and Retinopathy
Fernandes, R., & Reis, F. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00001-3 · Cited by 4 · see citing works
Self-citation
Protective effects of sitagliptin against cyclophosphamide-induced hepatorenal toxicity in rats: biochemical, histological, and immunohistochemical evaluation
Esmaeili, F., Moradi, H. R., Kazemipour, N., Abdinasab, M. H., Faraji, M., & Nazifi, S. (2026) · Comparative Clinical Pathology · doi:10.1007/s00580-026-03819-6 · Cited by 2
“Previous investigations have similarly demonstrated that DPP-4 inhibition attenuates apoptosis-related signaling and preserves cellular integrity in experimental models of tissue injury (Abd-Eldayem et al. 2024; Marques et al. 2014).”
Renoprotective Potency of Sitagliptin versus Pioglitazone in Type 2 Diabetic Patients: Impact on LncMIAT
Kandeil, M., Shaarawy, M. A., Mourad, H., & Mahmoud, M. O. (2023) · ACS Omega · doi:10.1021/acsomega.3c07008 · Cited by 2 · see citing works
Synergistic effects of sitagliptin and losartan against fipronil-induced hepatotoxicity in rats
Elazab, S., Samir, O., & Abass, M. (2021) · Veterinary World · doi:10.14202/vetworld.2021.1901-1907 · Cited by 2
Sitagliptin–Moringa oleifera coadministration did not delay the progression nor ameliorated functional and morphological anomalies in alloxan-induced diabetic nephropathy
Olurishe, C., Kwanashie, H., Zezi, A., Danjuma, N., & Mohammed, B. (2017) · Indian Journal of Pharmacology · doi:10.4103/ijp.ijp_832_16 · Cited by 2
“This is contrary to reports from previous studies, where very low doses of ST (5 and 10 mg/kg) had produced decreases in serum levels of urea in diabetic rats.[26] The difference in the present study where ST was used in therapeutic doses is likely related to the extremely high urinary concentrations that result from…”
ResultInfluential

Authors: Marques, C., Mega, C., Gonçalves, A., Rodrigues-Santos, P., Teixeira-Lemos, E., Teixeira, F., Fontes-Ribeiro, C., Reis, F., & Fernandes, R.
Affiliations: University of Coimbra (PT)
Centro de Estudos em Educação Tecnologia e Saúde (PT)
Institute of Immunology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
Corresponding author: Fernandes, Rosa
ORCID: Marques, Catarina
Mega, Cristina
Gonçalves, Andreia
Teixeira-Lemos, Edite
Teixeira, Frederico
Reis, Flávio
Fernandes, Rosa
Venue: Mediators of Inflammation
Publisher: Wiley
Published: 2014
Volume: 2014
Pages: 1-15
ISSN: 0962-9351 (ISSN-L)
1466-1861
DOI: 10.1155/2014/538737
PMC: PMC4000968
OpenAlex: W2105771613
Cited by: 126
References: 80
Citations by year: 2026: 5 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 15 · 2020: 15 · 2019: 10 · 2018: 11 · 2017: 21 · 2016: 15 · 2015: 8 · 2014: 1 · 2013: 1
FWCI: 12.07
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0/ (unspecified)
Locations: Mediators of Inflammation (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
Funders: Foundation for Science and Technology, Portugal (PEst-C/SAU/UI3282/2011, PEst-C/SAU/UI3282/2013, COMPETE)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords: sitagliptin, type 2 diabetes, diabetic nephropathy, DPP-4 inhibitors, glucagon-like peptide-1, GLP-1 receptor, renal inflammation, apoptosis, Bax/Bcl-2 ratio, Bid, TNF-α, IL-1β, tubulointerstitial injury, glomerular lesions, glycemic control, Zucker diabetic fatty rats
MeSH terms: Sitagliptin Phosphate, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Inflammation, Kidney, Pyrazines, Rats, Zucker, Triazoles, Tumor Necrosis Factor-alpha, Apoptosis, Rats, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors

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Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals

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