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

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 11; pp. 3205 - 3217
• Main Authors: Casemayou, Audrey, Fournel, Audren, Bagattin, Alessia, Schanstra, Joost, Belliere, Julie, Decramer, Stéphane, Marsal, Dimitri, Gillet, Marion, Chassaing, Nicolas, Huart, Antoine, Pontoglio, Marco, Knauf, Claude, Bascands, Jean-Loup, Chauveau, Dominique, Faguer, Stanislas
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.11.2017
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Adult; Animals; Basic Research; 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; HNF1B; acute kidney injury; PPARGC1A; mitochondria
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2016050508

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–1 β (HNF-1 β ) 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 β transcriptional network. In vitro , exposure of proximal tubule cells to the inflammatory cytokines IFN- γ and TNF- α led to inhibition of HNF-1 β transcriptional activity. Moreover, inhibition of HNF-1 β significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1 β 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 β 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.