Role of RARRES1 in diabetic kidney disease

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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.