Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression

Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glome...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-10, Vol.130 (10), p.5523-5535
Main Authors: Chen, Anqun, Feng, Ye, Lai, Han, Ju, Wenjun, Li, Zhengzhe, Li, Yu, Wang, Andrew, Hong, Quan, Zhong, Fang, Wei, Chengguo, Fu, Jia, Guan, Tianjun, Liu, Bichen, Kretzler, Matthias, Lee, Kyung, He, John Cijiang
Format: Article
Language:English
Subjects:
Apoptosis
Biomedical research
Biopsy
Cell death
Consortia
Creatinine
Datasets
Diabetes
Diabetes mellitus
Gene expression
Kidney diseases
Kinases
Nephropathy
Nephrotic syndrome
p53 Protein
Proteins
Renal function
Tumor necrosis factor-α
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Summary:Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCn40155