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Abstract: PO1721

Podocyte-Derived RARRES1 Aggravates Kidney Disease Progression by Inducing Both Glomerular and Tubular Injury

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Feng, Ye, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
  • Liu, Bi-Cheng, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai Department of Medicine, New York, New York, United States
Background

Our previous study demonstrates that the expression of retinoic acid receptor responder protein 1 (RARRES1) increases in glomeruli of patients with diabetic nephropathy (DN) and focal segmental glomerulosclerosis (FSGS). The glomerular expression of RARRES1 also correlates with eGFR slope and predicts glomerular disease progression. Single-cell RNA-sequencing of the kidney showed that RARRES1 expressed mostly in podocytes within the kidney. Mechanistically, WT-RARRES1 is cleaved into a soluble form which subsequently induces podocyte apoptosis whereas mutant RARRES1 with cleavage defect failed to induce podocyte apoptosis in vitro. Here, we further determined whether increased expression of WT-RARRES1 in the podocytes aggravated progression of glomerular disease.

Methods

Mice with podocyte-specific overexpression of human WT- RARRES1 or mutant RARRES1 with cleavage defect were generated and then subjected to aging, adriamycin (ADR) administration or streptozotocin (STZ) injection. To identify the role of podocyte-derived soluble RARRES1 in tubular cells, HK2 cells were treated with soluble RARRES1 obtained from podocyte supernatants.

Results

In vivo, podocyte-specific overexpression of WT-RARRES1 resulted in severe proteinuria and marked glomerular cell injury in mice with aging, adriamycin-induced nephropathy, or STZ-induced diabetic nephropathy as compared to the control mice with overexpression of mutant RARRES1. Interestingly, tubular vacuolation and interstitial injury were also observed in these mice with podocyte-specific overexpression of RARRES1. In addition, we showed that soluble RARRES1 collected from podocyte supernatants was endocytosed in HK2 cells to induce cellular injury. Similarly, cleaved form of human RARRES1 in the mice with podocyte-specific human RARRES1 overexpression was found in the tubular compartments, indicating that soluble RARRES1 generated from podocytes may act on tubular cells through glomeruli-tubule crosstalk.

Conclusion

Our study suggests that RARRES1 is a risk gene for glomerular disease progression through its direct effects in podocytes as well as indirect effects in tubular cells probably via glomeruli to tubules crosstalk.

Funding

  • NIDDK Support