Hepatocyte nuclear factor‐1β shapes the energetic homeostasis of kidney tubule cells

Abstract

Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b −/− ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b −/− cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

“…Secondly, in vitro and in vivo experiments have shown that HNF1β controls mitochondrial respiration in the PT [ 15 , 61 ]. Inhibition or KO of HNF1β in a human PT cell line resulted in either downregulation of Ppargc1a (important for mitochondrial biogenesis) and altered mitochondrial morphology or ATP reduction and increased glycolysis, respectively [ 15 , 61 ]. The kidney requires large quantities of ATP to maintain electrochemical gradients across membranes which are particularly important for transcellular ion transport [ 9 ].…”

Sexually dimorphic renal expression ofKlothois directed by a kidney-specific distal enhancer responsive to HNF1b

“…Among the transcription factors responsible for those changes, HNF1b is inextricably linked to kidney health (8). It plays a role in fetal development, ion transport and mitochondrial health, while human mutations of HNF1b result in various nephropathies (9, 10, 11, 12). Taken together, those insights into renal enhancer activity open new avenues of investigation, as in some cases, the usual gene deletion approach is not viable to dissect the gene’s role, and reducing gene expression through enhancer deletion can provide new understanding of clinically relevant mechanisms.…”

Sexually dimorphic renal expression of Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b

“…8 It plays a role in fetal development, ion transport and mitochondrial health, while human mutations of HNF1b result in various nephropathies. [9][10][11][12] Taken together, those insights into renal enhancer activity open new avenues of investigation, as in some cases, the usual gene deletion approach is not viable to dissect the gene's role, and reducing gene expression through enhancer deletion can provide new understanding of clinically relevant mechanisms.…”