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 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. , 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 promoter in mouse kidneys. We also demonstrated downregulation of renal expression in a patient with an germinal mutation. Thus, we propose that HNF-1 links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly PPARGC1A signaling. Our findings further strengthen the view of-related nephropathy as a mitochondrial disorder in adulthood.

Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

“…Indeed, accumulating evidence links mitochondrial dysfunction to the development and progression of diseases such as acute kidney injury, diabetic nephropathy and chronic kidney disease. [11][12][13][14][15][16][17] This is further supported by our recent finding that RPTC dysfunction is accompanied by decreased utilization of fatty acids by mitochondria and impaired ATP production. Notably, these effects are rescued by a peripheral blockade of CB 1 R, 9 in agreement with reports by others who describe a role for the eCB/CB 1 R system in modulating different aspects of mitochondrial physiology.…”

“…Thus, an impairment in mitochondrial bioenergetics may result in renal dysfunction. Indeed, accumulating evidence links mitochondrial dysfunction to the development and progression of diseases such as acute kidney injury, diabetic nephropathy and chronic kidney disease . This is further supported by our recent finding that RPTC dysfunction is accompanied by decreased utilization of fatty acids by mitochondria and impaired ATP production.…”

Hnf4ais required for the development of Cdh6-expressing progenitors into proximal tubules in the mouse kidney

“…62,63 Both PPARa/g and Hnf1a/b have been implicated in proximal tubule development and function, indicating that they are good candidate co-regulators of proximal tubule development. [64][65][66] PPAR transcription factors are known binding partners of RXR and one study predicted 17 common targets between Hnf4a and PPARa. 67 Hnf1b is expressed in all nephron segments [68][69][70][71][72] and Hnf1b deficiency in the nephron lineage of the mouse kidney leads to defects in nephron formation, particularly the proximal tubules, loops of Henle, and distal tubules.…”

HNF1B nephropathy has a slow-progressive phenotype in childhood—with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry

“…The cause of hyperuricemia in both ADTKD-UMOD and ADTKD-HNF1B is not well understood, but hyperuricemia seems to be a consequence of tubulointerstitial dysfunction. Novel experimental studies have linked HNF1B to mitochondrial energy metabolism in renal tubular cells [42] providing a possible link to transcellular substrate movements. More experimental work will be necessary for better defining the role of HNF1B in uric acid transport and metabolism.…”