Genomic integration of ERR?-HNF1? regulates renal bioenergetics and prevents chronic kidney disease.

ABSTRACT: Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERR?) and hepatocyte nuclear factor 1 beta (HNF1?) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERR? directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1?. Deletion of ERR? in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1? loss-of-function gene mutations. Moreover, ERR? expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERR? KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERR? in directing independent and HNF1?-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC6003475 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature