Kidney Week

Abstract: SA-OR58

Podocyte-Derived Soluble RARRES1: A Primary Instigator of CKD Progression via Direct Injury to Podocytes and Proximal Tubules

Session Information

• Glomerular Diseases: All about Podocytes
  October 26, 2024 | Location: Room 1, Convention Center
  Abstract Time: 05:00 PM - 05:10 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Feng, Ye, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Ye Feng, MD, PhD

• Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Zeguo Sun

• Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Jia Fu, MD, MS

• Zhong, Fang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Fang Zhong, MD, PhD

• Zhang, Weijia, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Weijia Zhang

• Liu, Bi-Cheng, Southeast University School of Medicine, Nanjing, Jiangsu, China

Bi-Cheng Liu, MD, PhD

• He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

John Cijiang He, MD, PhD, FASN

• Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Kyung Lee, PhD, FASN

Background

RARRES1 is a podocyte-enriched membrane protein, whose expression correlates with human glomerular disease progression. We previously showed that RARRES1 induces podocyte apoptosis to promote glomerulosclerosis. Interestingly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble form (sRARRES1), as cleavage mutant RARRES1 exerted no effects. As RARRES1 expression is upregulated in glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in glomerular diseases.

Methods

Mice with podocyte-specific overexpression of human wildtype-RARRES1 (Pod-RARRES1^WT) were generated and subjected to adriamycin-induced FSGS and streptozotocin-induced DKD. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. Wildtype and transgenic mice with cleavage-mutant RARRES1 (Pod-RARRES1^MT) overexpression served as controls.

Results

Pod-RARRES1^WTmice had significantly worsened glomerular injuries and kidney function in all three models, while the phenotype of Pod-RARRES1^MT mice was indistinguishable from those of wildtype control mice. Remarkably, a direct uptake of sRARRES1 was observed in proximal tubules of injured Pod-RARRES1^WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation in disease settings. Remarkably, the tubular uptake of sRARRES1 and injury was independent of albuminuria or glomerular injury, as RARRES1 podocyte expression alone was sufficient to induce tubular injury directly. scRNAseq analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) to be a podocyte-specific metalloproteinase responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo.

Conclusion

Our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

Funding

• NIDDK Support