# Role of RARRES1 in diabetic kidney disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $446,958

## Abstract

PROJECT SUMMARY
Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) in the US, and
podocyte injury is a key event in DKD and primary glomerular diseases. In vitro and in vivo studies with
experimental mouse models demonstrated a protective role of retinoic acid (RA) against podocyte injury in
glomerular diseases, but these findings had not been validated in human studies. Leveraging the glomerular
transcriptomic datasets of human primary glomerular disease available from the Nephrotic Syndrome Study
Network Consortium (NEPTUNE), we recently identified retinoic acid receptor responder protein 1 (RARRES1)
as a gene whose expression was negatively correlated with estimated glomerular filtration rate (eGFR) decline
and associated with worsened renal outcomes in patients with primary glomerular disease, suggesting that
RARRES1 is a risk gene for human glomerular disease. Since RA signaling had been shown to be largely
renoprotective against podocyte injury in experimental CKD models, these results suggested that RA signaling in
vivo may in fact confer dichotomous cytoprotective (RARRES1-independent) and cytopathic (RARRES1-
dependent) effects in the regulation of podocyte homeostasis. Indeed, our in vitro and in vivo findings show that
increased podocyte RARRES1 expression leads to podocytopathy in mice, whereas decreased RARRES1
mitigates podocyte injury and disease progression in experimental mouse model of FSGS. Mechanistically, the
cleavage of membrane-bound RARRES1 in its extracellular domain into a soluble form (sRARRES1) and its
subsequent endocytic uptake is required for RARRES1-mediated podocyte apoptosis. These results indicate a
critical role of RARRES1-mediated podocyte injury in glomerular disease, which were recently published in JCI
[Chen et al. 2020, PMID: 32634130]. Expanding on these results, we further posit that RARRES1 is a key
pathogenic inducer of podocyte loss and DKD progression. Since RARRES1 cleavage is critical for the podocyte
apoptosis in vivo, a better understanding of RARRES1 cleavage mechanism can be translated therapeutically to
attenuate podocyte loss in DKD, and ii) since sRARRES1 levels increase in the plasma and urine of DKD patients,
plasma and urinary sRARRES1 may serve as a prognostic biomarker of DKD progression. Therefore, in this
application we propose to 1) examine the mechanism of RARRES1 cleavage and its role in kidney cell injury in
vitro; 2) Examine the contribution of RARRES1 in DKD pathogenesis in vivo; and 3) Examine whether the
sRARRES1 detection can be utilized as a prognostic biomarker for future incidence or progression of DKD,
leveraging two cohorts (ISMMS BioMe biobank and ACCORD). Moreover, this proposal will address the current
knowledge gap on the dichotomous role of RA in podocyte homeostasis.

## Key facts

- **NIH application ID:** 10461883
- **Project number:** 5R01DK129467-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** John Cijiang He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,958
- **Award type:** 5
- **Project period:** 2021-08-04 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461883

## Citation

> US National Institutes of Health, RePORTER application 10461883, Role of RARRES1 in diabetic kidney disease (5R01DK129467-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461883. Licensed CC0.

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