Hepatocyte Nuclear Factor-1β 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 <i>γ</i> coactivator 1-<i>α</i> (PPARGC1A), a coactivator of the transcription factor PPAR-<i>γ</i> 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<i>β</i> (HNF-1<i>β</i>) 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<i>β</i> transcriptional network. <i>In vitro</i>, exposure of proximal tubule cells to the inflammatory cytokines IFN-<i>γ</i> and TNF-<i>α</i> led to inhibition of HNF-1<i>β</i> transcriptional activity. Moreover, inhibition of HNF-1<i>β</i> significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1<i>β</i> binding to the <i>Ppargc1a</i> promoter in mouse kidneys. We also demonstrated downregulation of renal <i>PPARGC1A</i> expression in a patient with an <i>HNF1B</i> germinal mutation. Thus, we propose that HNF-1<i>β</i> links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly <i>via</i> PPARGC1A signaling. Our findings further strengthen the view of <i>HNF1B</i>-related nephropathy as a mitochondrial disorder in adulthood.