Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease

Juanjuan Zhao, Katherine Lupino, Benjamin J. Wilkins, Chengxiang Qiu, Jian Liu, Yasuhiro Omura, Amanda L. Allred, Caitlin McDonald, Katalin Susztak, Grant D. Barish, Liming Pei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ 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 HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.

Original languageEnglish (US)
Pages (from-to)E4910-E4919
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number21
DOIs
StatePublished - May 22 2018

Keywords

  • ERRγ
  • Kidney
  • Mitochondria
  • Nuclear receptor
  • Renal reabsorption

ASJC Scopus subject areas

  • General

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