Abstract: FR-PO685
Glomerular-Tubular Cells Cross-Talk Mediated by Soluble RARRES1, a Podocyte-Secreted Protein
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Feng, Ye, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
Retinoic acid receptor responder protein 1 (RARRES1) is a transmembrane protein whose expression is found mainly in podocytes and its expression is correlated with human glomerular disease progression. Our previous study also showed that extracellular cleavage of RARRES1 results in soluble form (sRARRES1), which is taken up via endocytosis to cause podocyte injury. Importantly, sRARRES1, but not full-length RARRES1, is pathogenic, as RARRES1 mutant with cleavage defect fails to induce podocyte injury. Therefore, we further determined the mechanism of RARRES1 cleavage to injure podocytes in an autocrine manner and whether podocyte-secreted sRARRES1 may injure tubular cells in a paracrine manner.
Methods
Human primary tubular epithelial cells were treated with sRARRES1 obtained from the supernatants of human podocytes with RARRES1 overexpression. Mice with podocyte-specific overexpression of human wildtype RARRES1 or RARRES1 cleavage mutant were generated and used for the study.
Results
We previously demonstrated that RARRES1 is cleaved by the MMP protease family. Among MMPs, multiple kidney scRNAseq datasets identified MMP23b to be highly and uniquely expressed in podocytes. In cultured human podocytes, TNF-α leads to enhanced MMP23b mRNA and protein expression, and MMP23b knockdown partially blocked RARRES1 cleavage. Treatment of tubular cells with purified sRARRES1 from podocyte supernatants induced tubular cell injury following its endocytic uptake. Interestingly, KIM-1 knockdown reduced tubular uptake of sRARRES1. Markers of ER stress were enhanced in tubular cells with sRARRES1 uptake in vitro. Consistently, kidneys of aged mice with podocyte-specific RARRES1 overexpression showed marked increase in ER stress and tubular injury markers, in the absence of significant proteinuria, suggesting that podocyte-derived sRARRES1 induces tubular cell ER stress and injury via glomerulo-tubular crosstalk.
Conclusion
Increased podocyte RARRES1 expression in glomerular disease results increased cleavage and uptake of sRARRES1 that results in autocrine podocyte injury as well as significant paracrine tubular cell injury, suggesting an important role of RARRES1 in podocyte-tubular cell crosstalk in kidney disease.
Funding
- NIDDK Support