Calcineurin inhibitors ameliorate PAN-induced podocyte injury through the NFAT-Angptl4 pathway

The Journal of Pathology
Xiujin ShenHong Jiang

Abstract

Podocyte injury plays a vital role in proteinuria and nephrotic syndrome. Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully understood. Angiopoietin-like-4 (ANGPTL4) is a secreted protein that mediates proteinuria in podocyte-related nephropathy. In this study, we established a puromycin aminonucleoside (PAN)-induced minimal-change disease (MCD) rat model and a cultured podocyte injury model. We found that CaN inhibitors protected against PAN-induced podocyte injury, accompanied by an inhibition of Nfatc1 and Angptl4 both in vivo and in vitro. Nfatc1 overexpression and knockdown experiments indicated that Angptl4 was regulated by Nfatc1 in podocytes. ChIP assays further demonstrated that Nfatc1 increased Angptl4 expression by binding to the Angptl4 promoter. In addition, overexpression and knockdown of Angptl4 revealed that Angptl4 directly induced rearrangement of the cytoskeleton of podocytes, reduced the expression of synaptopodin, and enhanced PAN-induced podocyte apoptosis. Furthermore, in a cohort of 83 MCD and 94 membranous nephropathy (MN) patients, we found increased expression of serum ANGPTL4 compared to 120 healthy controls, and there were close...Continue Reading

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