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

ABSTRACT: 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 ? coactivator 1-? (PPARGC1A), a coactivator of the transcription factor PPAR-? 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-1? (HNF-1?) 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-1? transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-? and TNF-? led to inhibition of HNF-1? transcriptional activity. Moreover, inhibition of HNF-1? significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1? 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-1? 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.

SUBMITTER: Casemayou A 

PROVIDER: S-EPMC5661272 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature