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Kidney Week

Abstract: PO1967

Soluble RARRES1 Induces Apoptosis of Podocytes to Promote Progression of Kidney Disease

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Chen, Anqun, Division of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
  • Feng, Ye, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, United States
  • Li, Yu, Division of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
  • Wei, Chengguo, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, United States
  • Guan, Tianjun, Division of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China
  • Lee, Kyung, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, United States
  • He, John Cijiang, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, United States
Background

Podocyte loss is a major event leading to the progression of focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN). Here, we found that retinoic acid receptor responder protein 1 (RARRES1) contributes to the podocyte loss in FSGS and DN.

Methods

We determined the role of RARRES1 in human and mouse with FSGS and DN. We investigated the mechanisms of RARRES1 in cultured human podocytes.

Results

The expression of RARRES1 increased in the glomeruli of patients with FSGS and DN and correlated with the eGFR. Single-cell RNA-sequencing of the kidney showed that RARRES1 expressed highly in podocytes. Immunostaining confirmed that podocyte expression of RARRES1 increased in patients with DN and FSGS as compared to MCD. RARRES1 expression was strongly induced by TNF-α in cultured human podocytes. RNA-sequencing of podocytes with RARRES1 overexpression revealed genes enriched in apoptosis. RARRES1 was cleaved into a soluble RARRES1 and the cleavage site was mapped at the aa70. Overexpression of wild RARRES1 or adding soluble RARRES1 in cultured human podocytes induced apoptosis, while overexpression of RARRES1 cleavage mutant lost the apoptotic effect. Further, we showed that soluble RARRES1 underwent endocytosis to interact with intracellular RIOK1, leading to the activation of p53 and apoptosis in podocytes. In vivo, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria in mice, while the overexpression of RARRES1 cleavage mutant had no renal phenotype. Finally, knockdown of RARRES1 in podocytes ameliorated kidney injury in mice with adriamycin-induced nephropathy.

Conclusion

we demonstrate a new role and mechanism of RARRES1 in regulation of podocyte apoptosis in glomerular disease, as summarized in the Figure: TNFα induces expression of RARRES1, which is cleaved, then undergoes endocytosis to interact with intracellular RIOK1, leading to the activation of p53 and apoptosis. High RARRES1 expression promotes the progression of FSGS and DKD.

Funding

  • Government Support - Non-U.S.