Insig1 deletion in proximal tubular deregulates Aldh1a1 to consume NAD+ and contributes to renal fibrosis

Abstract

Abstract Profibrotic proximal tubules (PTs) were identified as a unique phenotype of PTCs in renal fibrosis. Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insig1 is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered the pathogenic effect of PTC-specific Insig1 deficiency on renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Insig1 deletion boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, and accelerating renal fibrosis. We identified nicardipine as a selective inhibitor of Aldh1a1-restored NAD+ and ER homeostasis, which attenuated renal fibrosis. Together, our findings support Insig1 as a new therapeutic target for CKD.