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J Am Soc Nephrol. 2017 Nov;28(11):3205-3217. doi: 10.1681/ASN.2016050508. Epub 2017 Jul 24.

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

Author information

1
Institut National de la Santé et de la Recherche Médicale, U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.
2
University Toulouse III Paul-Sabatier, Toulouse, France.
3
Institut National de la Santé et de la Recherche Médicale U1220, Institut de Recherche en Santé Digestive (IRSD), CHU Purpan-BP3028, 31024 Toulouse Cedex 3.
4
Laboratoire d'Expression Génique, Développement et Maladies, Département Développement, Reproduction et Cancer, Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.
5
Department of Nephrology and Organ Transplantation, Center for Rare Renal Diseases, University Hospital of Toulouse, Toulouse, France.
6
Department of Nephrology, Internal Medicine and Hypertension, Center for Rare Renal Diseases, Children' Hospital, University Hospital of Toulouse, Toulouse, France.
7
Department of Medical Genetics, Hôpital Purpan, University Hospital of Toulouse, Toulouse, France; and.
8
Institut National de la Santé et de la Recherche Médicale, U1188, DéTROI (Diabète Athérothrombose Thérapies Réunion Océan Indien), University of La Réunion.
9
Institut National de la Santé et de la Recherche Médicale, U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; stanislas.faguer@inserm.fr.

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 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.

KEYWORDS:

HNF1B; PPARGC1A; acute kidney injury; mitochondria

PMID:
28739648
PMCID:
PMC5661272
DOI:
10.1681/ASN.2016050508
[Indexed for MEDLINE]
Free PMC Article

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