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

Abstract

Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor essential for the development and function of the kidney. Mutations in and deletions of HNF1β cause autosomal dominant tubule interstitial kidney disease (ADTKD) subtype HNF1β, which is characterized by renal cysts, diabetes, genital tract malformations, and neurodevelopmental disorders. Electrolyte disturbances including hypomagnesemia, hyperuricemia, and hypocalciuria are common in patients with ADTKD-HNF1β. Traditionally, these electrolyte disturbances have been attributed to HNF1β-mediated transcriptional regulation of gene networks involved in ion transport in the distal part of the nephron including FXYD2, CASR, KCNJ16, and FXR. In this review, we propose additional mechanisms that may contribute to the electrolyte disturbances observed in ADTKD-HNF1β patients. Firstly, kidney development is severely affected in Hnf1b-deficient mice. HNF1β is required for nephron segmentation, and the absence of the transcription factor results in rudimentary nephrons lacking mature proximal tubule, loop of Henle, and distal convoluted tubule cluster. In addition, HNF1β is proposed to be important for apical-basolateral polarity and tight junction integrity in the kidney. Interestingly, cilia formation is unaffected by Hnf1b defects in several models, despite the HNF1β-mediated transcriptional regulation of many ciliary genes. To what extent impaired nephron segmentation, apical-basolateral polarity, and cilia function contribute to electrolyte disturbances in HNF1β patients remains elusive. Systematic phenotyping of Hnf1b mouse models and the development of patient-specific kidney organoid models will be essential to advance future HNF1β research.

Keywords: Apical-basolateral polarity; Electrolyte disturbances; HNF1β; Kidney development; Transcriptional regulation.

Fig. 1

HNF1β regulates expression of channels, and transporters in all segments of the nephron. HNF1β regulates target genes involved in electrolyte handling in the PT including TMEM27 encoding the amino acid transport regulator (Collectrin); SLC17A1 encoding the Na-phosphate transporter 1 (NPT1); SLC22A6, SLC22A8, and SLC22A11 encoding the organic anion transporters (OAT1, OAT3, OAT4); and SLC22A12 encoding the renal urate transporter (URAT1); in the TAL including SLC12A1 encoding the Na⁺-K⁺-2Cl⁻ co-transporter (NKCC2); UMOD encoding uromodulin (UMOD); CASR encoding the calcium sensing receptor (CaSR); and CLDN16 encoding Claudin 16; in the DCT including KCNJ16 encoding the subunit of the inward rectifier K⁺ channel (Kir5.1) and FXYD2 encoding the Na⁺-K⁺-ATPase subunit gamma; in the CD including TMEM27 and NR1H4 encoding the farnesoid X nuclear receptor (FXR). In return, transcription factor FXR regulates expression of AQP2 in the CD. PT proximal tubules, DCT distal convoluted tubule, TAL thick ascending loop of Henle, CD collecting duct, OA⁻ organic anion, DC⁻ dicarboxylate

Fig. 2

HNF1β is required for UB branching and nephron segmentation. Schematic representation of different stages of mouse metanephric nephron development. At E10.5, kidney development starts with the outgrowth of the UB into the MM. HNF1β is essential for normal branching of the UB that eventually will form the collecting duct system. Around E12.5, cells of the cap mesenchyme polarize into pretubular aggregates that will form renal vesicles which require MET. Whether HNF1β is involved in this early stage of nephrogenesis is not yet conclusive. Subsequently, renal vesicles differentiate into comma and S-shaped bodies. Hnf1b KO mice develop S-shaped bodies that lack the epithelial bulge that will give rise to the proximal and Henle’s loop tubule in the WT situation. Eventually at E17.5, part of the S-shaped body will associate with capillaries to form the glomerulus and other parts will form the nephron tubule. WD Wolffian duct, UB ureteric bud, MM metanephric mesenchyme, MET mesenchymal-epithelial transition