Hepatocyte Nuclear Factor-1 β Controls Mitochondrial Respiration in Renal Tubular Cells

J Am Soc Nephrol. 2017 Nov;28(11):3205-3217. doi: 10.1681/ASN.2016050508. Epub 2017 Jul 24.


AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A), a coactivator of the transcription factor PPAR-γ that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1β (HNF-1β) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1β transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-γ and TNF-α led to inhibition of HNF-1β transcriptional activity. Moreover, inhibition of HNF-1β significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1β binding to the Ppargc1a promoter in mouse kidneys. We also demonstrated downregulation of renal PPARGC1A expression in a patient with an HNF1B germinal mutation. Thus, we propose that HNF-1β links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly via PPARGC1A signaling. Our findings further strengthen the view of HNF1B-related nephropathy as a mitochondrial disorder in adulthood.

Keywords: HNF1B; PPARGC1A; acute kidney injury; mitochondria.

Publication types

  • Case Reports

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / metabolism*
  • Adult
  • Animals
  • Hepatocyte Nuclear Factor 1-beta / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 1-beta / physiology*
  • Humans
  • Kidney Tubules, Proximal / metabolism*
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / physiology


  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Hepatocyte Nuclear Factor 1-beta