Journal of the American Society of Nephrology : JASN
Journal of the American Society of Nephrology : JASN
5 years ago

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

Bascands JL, Huart A, Bagattin A, Chauveau D, Knauf C, Chassaing N, Schanstra J, Faguer S, Marsal D, Decramer S, Belliere J, Gillet M, Fournel A, Casemayou A, Pontoglio M
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.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28739648

DOI: PubMed:28739648

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