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Cited by 48Renin-Angiotensin System StudiesCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; none of the 52 sources its claims cite is checked for support yet.

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Open access
Lu, Xifeng, Meima, Marcel E., Nelson, Jessica K., Sorrentino, Vincenzo, Loregger, Anke, Scheij, Saskia, Dekkers, Dick H.W., Mulder, Monique T., Demmers, Jeroen A.A., M-Dallinga-Thie, Geesje, Zelcer, Noam, Danser, A.H. Jan·2016·Circulation Research
DOI 10.1161/circresaha.115.306799
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Abstract

Rationale: The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin–angiotensin system–independent functions for (P)RR related to its association with the vacuolar H + -ATPase. Objective: To uncover renin–angiotensin system–independent functions of the (P)RR. Methods and Results: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. Conclusions: Our study identifies a renin–angiotensin system–independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Using an unbiased proteomics screen, the authors identify the (pro)renin receptor [(P)RR] as a novel post-transcriptional regulator of LDL metabolism through interaction with sortilin 1 (SORT1). (P)RR depletion reduces SORT1 and LDLR protein abundance, lowers cellular LDL uptake, and points to a role in LDLR trafficking rather than gross endocytic failure.

Key findings

  • TAP-based proteomics in HEK293 cells identified 40 proteins copurifying with N-terminally TAP-tagged (P)RR in 2 independent purifications; SORT1 had the highest Mascot score and was not found in the CRAPome. Endogenous (P)RR–SORT1 interaction was validated by coimmunoprecipitation, whereas TRAF4 did not coimmunoprecipitate with endogenous (P)RR.
  • Silencing (P)RR decreased SORT1 protein abundance by 42% without changing SORT1 transcript levels. It also reduced total LDLR and cell-surface LDLR and decreased LDL uptake: approximately 2-fold in A431 cells, 40% in HepG2 cells, and similarly in Huh7 cells; the effect was minimal in LDLR-deficient LDLA7 CHO cells.
  • Combined silencing of (P)RR and SORT1 did not additively reduce LDL uptake compared with either alone, and SORT1 silencing also reduced LDLR abundance and LDL uptake. Lysosomotropic agents bafilomycin A1, NH4Cl, and chloroquine rescued LDLR levels after (P)RR silencing but did not rescue SORT1.
  • Transferrin and EGF uptake were not decreased after (P)RR silencing, arguing against a gross defect in clathrin-dependent endocytosis.

Methods

  • Cell culture and transfection: HEK293, A431, Huh7, HepG2, and LDLA7 CHO cells were maintained under standard conditions; siRNA and plasmid transfections were performed with Lipofectamine 2000, JetPrime, or RNAiMax, generally after sterol depletion to increase LDLR expression.
  • Proteomics and protein analysis: (P)RR interactome was mapped in HEK293 cells using a TAP-based approach with 2 independent purifications and compared with CRAPome; coimmunoprecipitation, immunoblotting, and quantitative PCR were used to validate interactions and expression changes.
  • Functional assays and statistics: LDL uptake was measured with DyLight 488-labeled LDL; cell-surface LDLR was measured by FACS; surface-biotinylated LDLR was followed over time; lysosomotropic agents were tested. Data are mean±SEM, with one-way ANOVA plus Bonferroni correction or Student’s t test; P<0.05 was considered significant.

Limitations

  • The paper states that siRNA was used to suppress (P)RR, whereas prior studies used Cre-Lox genetic ablation, so minimal (P)RR levels may remain. It also states that the mechanism underlying reduced SORT1 protein after (P)RR silencing remains currently unknown.
  • The paper states that future studies are needed to assess the full spectrum of proteins regulated by the (P)RR–SORT1 interaction and to elucidate the role of (P)RR in lipoprotein metabolism in vivo.
  • Evident from the text: the findings are based on cultured cell lines, with no in vivo or human data; the proteomic screen used a heterologous N-terminally TAP-tagged (P)RR and many identified proteins were also high-frequency CRAPome contaminants.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/circresaha.115.306799

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 52 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Silencing (P)RR reduces LDL uptake in A431 and HepG2 cells cultured in complete medium containing lipoproteins.

    “Silencing (P)RR also reduced LDL uptake in A431 and HepG2 cells when these were cultured in complete medium (ie, medium containing lipoproteins), even though overall uptake was much lower when compared with that in sterol-depleted cells (Online Figure IIB and IIC).”
    Quote in the paperSubstantial claim
  • Findingown data

    (P)RR interacts with SORT1.

    “(Pro)renin receptor ([P]RR) interacts with sortilin-1 (SORT1) and regulates its protein abundance.”
    • Also stated in: § Summary · plain
      “coimmunoprecipitation of (P)RR with SORT1, but not with tumor necrosis factor receptor-associated factor 4 (TRAF4).”
    • Also stated in: § Additional information · plain
      “we found that it interacts with sortilin-1, a recently identified receptor for lowdensity lipoprotein.”
    Quote in the paperSubstantial claim
  • Findingown data

    Reducing (P)RR mRNA levels by approximately 90% in A431 cells results in a 2-fold decrease in LDL uptake.

    “In A431 cells, reducing (P)RR mRNA levels (by ≈90%) resulted in a 2-fold decrease in LDL uptake (Figure 2A-2C).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the absence of added lipoproteins, disappearance of surface-biotinylated LDLR is negligible.

    “In the absence of added lipoproteins, disappearance of labeled LDLR was negligible (not shown).”
    Quote in the paperSubstantial claim
  • Findingreasoning

    Silencing (P)RR reduces cellular LDL uptake.

    “thereby reducing the cellular uptake of low-density lipoprotein.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 29
  • Probably not a substantial claim. 19

  • It may state two separate claims as one.

    Findingown data

    Silencing SORT1 reduces cellular LDLR abundance to an extent comparable with (P)RR silencing and attenuates LDL uptake.

    “Unexpectedly, in these experiments we found that silencing SORT1 also effectively reduced cellular LDLR abundance to an extent comparable with that achieved by (P)RR silencing, and as a consequence also resulted in attenuated LDL uptake (Figure 3G; Online Figure IIB-IIE).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Transferrin uptake in A431 and HepG2 cells is not decreased after (P)RR silencing; it is slightly increased in A431 cells.

    “Consistent with this, and in contrast to the observed effects on LDL uptake, transferrin uptake in A431 and HepG2 cells was not decreased (Figure 2E and 2F; Online Figure IIIB).In fact, transferrin uptake was slightly increased in A431 cells after (P)RR silencing (Figure 2F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    SORT1 is the candidate with the highest Mascot score in the (P)RR interactome and is not found in the CRAPome.

    “From the identified proteins, SORT1 is the candidate with the highest Mascot score, and it is not found in the CRAPome.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In LDLA7 cells, silencing (P)RR or SORT1 significantly reduces LDL uptake, but the reduction is minimal and attenuated compared with the effect in other cells tested.

    “Overall LDL uptake in LDLA7 cells is low, but nevertheless silencing (P) RR or SORT1 significantly reduced LDL uptake in these cells.However, this reduction was minimal and attenuated in comparison with the effect that silencing these genes had in the other cells tested (Figure 3D, and compare with Figure 2C and 2D)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Silencing (P)RR in A431 cells does not influence abundance of either the transferrin receptor or the EGF receptor.

    “Silencing of (P)RR expression in A431 cells did not influence abundance of either the transferrin receptor or the EGF receptor (Online Figure IIIA).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingcitation

    Many proteins found in the (P)RR interactome, especially transporters, are also present at high frequency in other purifications in the CRAPome.

    “Many proteins found in our profile, especially transporters, are also present at high frequency in other purifications in the CRAPome.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    SORT1 depletion leads to a comparable reduction in cellular LDL uptake and decreased (P)RR abundance reciprocally.

    “Similarly, SORT1 depletion led to a comparable reduction in cellular LDL uptake and decreased (P)RR abundance reciprocally.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The (P)RR-SORT1 interaction controls LDLR protein stability and LDL uptake.

    “The (Pro)renin receptor ([P]RR)sortilin-1 (SORT1) interaction controls lowdensity lipoprotein (LDL) receptor (LDLR) protein stability and LDL uptake.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In LDLA7 cells, silencing (P)RR reduces SORT1 abundance, and silencing SORT1 reduces (P)RR abundance.

    “Similar to the other cell lines, silencing (P)RR expression reduced SORT1 abundance in LDLA7 cells, and vice versa, implying that a functional (P)RR-SORT1 interaction does not require the presence of the LDLR (Figure 3C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR silencing reduces LDLR cell-surface density without affecting SORT1 and LDLR mRNA expression.

    “and LDLR cell-surface density (Figures 3E and 3F) without affecting SORT1 and LDLR mRNA expression (Online Figure IVC and IVD).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    (P)RR silencing successfully suppresses (P)RR mRNA levels and does not affect SORT1 mRNA levels.

    “(P)RR silencing in HEK293 cells successfully suppresses (P) RR mRNA levels, and does not affect SORT1 mRNA levels; n=6, ***P<0.001.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Depletion of the (P)RR results in decreased protein levels of V-ATPase subunits, impaired acidification of intracellular compartments, and defects in autophagy.

    “Depletion of the (P)RR results in decreased protein levels of V-ATPase subunits, impaired acidification of intracellular compartments, and defects in autophagy.[12][13][14]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    SORT1 has been identified as an important determinant of LDL metabolism and of circulating levels of LDL in humans.

    “SORT1 is implicated in several cellular functions, 26,27 and it has recently been identified as an important determinant of LDL metabolism, [28][29][30] and of circulating levels of LDL in humans.29,31”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    (Pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H+-ATPase (V-ATPase).

    “Recently, (pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H + -ATPase (V-ATPase).9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    The main finding of the study is the identification of (P)RR as a post-transcriptional regulator of LDLR abundance and LDL uptake into cells, plausibly by regulating trafficking of the receptor to the plasma membrane.

    “The main finding of this study is the identification of (P)RR as a post-transcriptional regulator of LDLR abundance of LDL uptake into cells, plausibly by regulating trafficking of the receptor to the plasma membrane.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    The finding that SORT1 regulates LDLR protein levels is consistent with recent reports demonstrating that SORT1 deficiency leads to increased plasma LDL cholesterol and provides an additional mechanism that may contribute to this outcome.

    “This finding is consistent with recent reports demonstrating that SORT1 deficiency leads to increased plasma LDL cholesterol, 29,40 and provides an additional mechanism that may contribute to this outcome.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [40]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    Overexpression of SORT1 is not sufficient to overcome degradation of the LDLR induced by silencing (P)RR, indicating that this outcome is not solely dependent on reduced SORT1 protein.

    “However, this was not sufficient to overcome degradation of the LDLR induced by silencing (P)RR, indicating that this outcome is not solely dependent on reduced SORT1 protein.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Silencing of SORT1 results in a less pronounced increase in plasma LDL-cholesterol on an Ldlr-/- background.

    “or silencing of SORT1 resulted in a less pronounced increase in plasma LDLcholesterol on a Ldlr -/-background.29,41”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [41]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    (P)RR depletion affects LDL metabolism in multiple cell lines, suggesting that the (P)RR is a common regulator of LDL metabolism.

    “Taken together, these data show that (P)RR depletion affects LDL metabolism in multiple cell lines, suggesting that the (P)RR is a common regulator of LDL metabolism.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Regulation of LDLR by (P)RR is a post-transcriptional event culminating in lysosomal degradation of LDLR.

    “Our study demonstrates that regulation of the LDLR by the (P)RR is a post-transcriptional event culminating in lysosomal degradation of the LDLR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    TRAF4 can mediate activation of Erk1/2, Akt, and Wnt/β-catenin signaling, all of which have been recently suggested to be modulated by (P)RR.

    “Tumor necrosis factor receptor-associated factor 4 (TRAF4), despite having a Mascot score in the lower range was another attractive candidate, as it can mediate activation of Erk1/2, Akt, and Wnt/β-catenin signaling, [23][24][25] all of which have been”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    (P)RR depletion does not grossly attenuate clathrin-dependent endocytosis and differentially affects endocytosis of cargo, largely attenuating LDL uptake yet sparing EGF and transferrin internalization.

    “Taken together, these results indicate that (P)RR depletion does not grossly attenuate clathrin-dependent endocytosis and that (P)RR differentially affects endocytosis of cargo, largely attenuating LDL uptake yet sparing EGF and transferrin internalization.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    SORT1 can directly bind LDL and mediate LDL internalization in hepatocytes and macrophages.

    “Recent studies from the Rader Laboratory have shown that SORT1 can directly bind LDL and mediate LDL internalization in hepatocytes 28 and macrophages.34”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [34]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In experimental assays, (pro)renin-(P)RR signaling results in extracellular signal-regulated kinase 1/2 (Erk1/2) activation and upregulation of profibrotic factors such as transforming growth factor β, collagen, and fibronectin.

    “In experimental assays (pro)renin-(P)RR signaling results in extracellular signal-regulated kinase 1/2 (Erk1/2) activation, and as a consequence upregulation of profibrotic factors, such as transforming growth factor β, collagen, and fibronectin.[2][3][4][5][6]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    (P)RR is a previously unrecognized regulator of LDL metabolism, which specifically regulates cellular LDL uptake by modulating LDLR protein abundance.

    “we report that the (P)RR is a previously unrecognized regulator of LDL metabolism, which specifically regulates cellular LDL uptake by modulating LDLR protein abundance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: (P)RR has renin-angiotensin system-independent functions.

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    V-ATPases are multisubunit complexes expressed virtually in all cell types and play an important role in protein trafficking, receptor recycling, and lysosomal degradation by acidifying intracellular compartments.

    “V-ATPases are multisubunit complexes, and they are expressed virtually in all cells types.They play an important role in protein trafficking, receptor recycling, and lysosomal degradation by acidifying intracellular compartments.10,11”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The (P)RR is required for both prorenin-dependent and prorenin-independent regulation of V-ATPase activity in collecting duct cells.

    “Accordingly, we previously reported that the (P)RR is required for both prorenin-dependent and proreninindependent regulation of V-ATPase activity in collecting duct cells.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The functional interaction of (P)RR and SORT1 serves to ensure proper trafficking of nascent LDLR to the plasma membrane.

    “an alternative explanation for our observations may be that the functional interaction of the (P)RR and SORT1 serves to ensure proper trafficking of nascent LDLR to the plasma membrane.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Sortilin-1 is a receptor for low-density lipoprotein.

  • It may state two separate claims as one.

    Interpretationown data

    Reversal by lysosomotropic agents indicates an intact endolysosomal pH gradient and functional lysosomes.

    “indicating the existence of an intact endolysosomal pH gradient and functional lysosomes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Endocytosis of LDL via the LDLR pathway is a clathrin-dependent process.

    “Endocytosis of LDL via the LDLR pathway is a clathrindependent process.32”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The (P)RR has been implicated in canonical Wnt and PCP signaling.

    “The (P)RR has been also recently implicated in canonical Wnt and PCP signaling, [16][17][18] emphasizing the notion that our understanding of (P)RR function remains incomplete.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [18]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    SORT1 controls LDLR activity.

    “The ability of SORT1 to control LDLR activity hints that it may influence efficacy of statins by regulating LDLR activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    SORT1 controls hepatic very low-density lipoprotein secretion and can bind and internalize LDL directly, serving as a major regulator in determining plasma LDL levels.

    “SORT1 controls hepatic very low-density lipoprotein secretion, and can also bind and internalize LDL directly, thereby serving as a major regulator in determining plasma LDL levels.28,29,34”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [34]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Genetic variances in the SORT1 locus are associated with the LDL-cholesterol response to statin therapy.

    “a recent meta-analysis study found that genetic variances in the SORT1 locus are associated with the LDL-cholesterol response to statin therapy.42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    SORT1 promotes both apolipoprotein B secretion and degradation in hepatocytes.

    “SORT1 has been demonstrated to promote both apolipoprotein B secretion and degradation in hepatocytes.28,48”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisenone given

    Sortilin-1 controls LDL receptor protein abundance.

    “Sortilin-1 not only acts as a receptor for low-density lipoprotein, but also controls LDL receptor protein abundance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    SORT1 has an established role in intracellular trafficking of apolipoprotein B, PCSK9, Trk, and Glut4.

    “Given the established role of SORT1 in intracellular trafficking of apolipoprotein B, proprotein convertase subtilisin/kexin type 9, Trk, and Glut4, 28,[43][44][45]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [43]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Depleting (P)RR in podocytes decreases the level of V-ATPase subunits, leading to autophagosomal defects.

    “previous studies demonstrated that depleting the (P)RR in podocytes decreases the level of V-ATPase subunits leading to autophagosomal defects.13,14”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Macrophages lacking PRR do not display altered acidification and phagolysosomal defects.

    “Kissing et al 47 recently reported that macrophages lacking PRR do not display altered acidification and phagolysosomal defects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

39 of 39

  • The paper relies on this without support.

    (P)RR has renin-angiotensin system-independent functions.

    “The (P)RR is now believed to largely have renin-angiotensin system-independent functions.”

  • The paper relies on this without support.

    Sortilin-1 is a receptor for low-density lipoprotein.

    “sortilin-1, a recently identified receptor for lowdensity lipoprotein.”
2 of 2

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

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.

  • Figure 3D is described as both an immunoblot and an LDL uptake measurement

    Minor

    The caption first includes panel D among the immunoblot panels, then identifies panel D as a quantitative LDL uptake measurement.

1 of 1

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Metadata

Authors
Lu, X., Meima, M. E., Nelson, J. K., Sorrentino, V., Loregger, A., Scheij, S., Dekkers, D. H. W., Mulder, M. T., Demmers, J. A. A., M-Dallinga-Thie, G., Zelcer, N., & Danser, A. H. J.
Affiliations
  • Shenzhen University (CN)
  • From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.),...
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-01-22
Volume
118
Issue
2
Pages
222-229
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.115.306799
OpenAlex
W2172668126
Cited by
48
References
48
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 5
FWCI
2.95
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • National University of Singapore (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Funders
  • National Natural Science Foundation of China
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Top Institute Pharma
  • FP7 Ideas: European Research Council (617376)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Keywords
prorenin receptor, low density lipoprotein metabolism, LDL receptor, SORT1, protein-protein interaction, hepatocytes, LDL uptake, post-transcriptional regulation, protein degradation, lysosomal degradation, bafilomycin A1, vacuolar H+-ATPase
MeSH terms
Prorenin Receptor, Sortilin, Animals, Cricetulus, Endocytosis, Humans, Lipoproteins, LDL, Protein Processing, Post-Translational, Receptors, Cell Surface, Receptors, LDL, Transfection, CHO Cells, Hepatocytes, Vacuolar Proton-Translocating ATPases, Adaptor Proteins, Vesicular Transport, RNA Interference, Proteomics, Chromatin Immunoprecipitation, Hep G2 Cells, HEK293 Cells, Proteolysis

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.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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