1. Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.
- Author
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Feng Y, Sun Z, Fu J, Zhong F, Zhang W, Wei C, Chen A, Liu BC, He JC, and Lee K
- Subjects
- Animals, Humans, Male, Mice, Apoptosis, Disease Models, Animal, Endocytosis, Membrane Proteins metabolism, Membrane Proteins genetics, Mice, Inbred C57BL, Mice, Transgenic, Diabetic Nephropathies pathology, Diabetic Nephropathies metabolism, Diabetic Nephropathies genetics, Diabetic Nephropathies etiology, Disease Progression, Glomerulosclerosis, Focal Segmental pathology, Glomerulosclerosis, Focal Segmental metabolism, Glomerulosclerosis, Focal Segmental genetics, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Podocytes metabolism, Podocytes pathology
- Abstract
Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1
WT ) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT ) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence 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) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, 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., (Copyright © 2024 International Society of Nephrology. All rights reserved.)- Published
- 2024
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