New insights into the role of HNF-1β in kidney (patho)physiology

Abstract

Hepatocyte nuclear factor-1β (HNF-1β) is an essential transcription factor that regulates the development and function of epithelia in the kidney, liver, pancreas, and genitourinary tract. Humans who carry HNF1B mutations develop heterogeneous renal abnormalities, including multicystic dysplastic kidneys, glomerulocystic kidney disease, renal agenesis, renal hypoplasia, and renal interstitial fibrosis. In the embryonic kidney, HNF-1β is required for ureteric bud branching, initiation of nephrogenesis, and nephron segmentation. Ablation of mouse Hnf1b in nephron progenitors causes defective tubulogenesis, whereas later inactivation in elongating tubules leads to cyst formation due to downregulation of cystic disease genes, including Umod, Pkhd1, and Pkd2. In the adult kidney, HNF-1β controls the expression of genes required for intrarenal metabolism and solute transport by tubular epithelial cells. Tubular abnormalities observed in HNF-1β nephropathy include hyperuricemia with or without gout, hypokalemia, hypomagnesemia, and polyuria. Recent studies have identified novel post-transcriptional and post-translational regulatory mechanisms that control HNF-1β expression and activity, including the miRNA cluster miR17 ∼ 92 and the interacting proteins PCBD1 and zyxin. Further understanding of the molecular mechanisms upstream and downstream of HNF-1β may lead to the development of new therapeutic approaches in cystic kidney disease and other HNF1B-related renal diseases.

Keywords: Development; Hepatocyte nuclear factor-1β; Ion transport; Metabolism; Polycystic kidney disease.

Figure 1. HNF1-β is required for UB branching, initiation of nephrogenesis, and nephron segmentation

Schematic showing the major stages of kidney development. HNF1-β-expressing cells are depicted in light pink. At E10.5, the UB emerges from the WD upon signaling from the MM. Starting from E12.5, HNF1-β is essential for UB branching. In developing nephrons, HNF1-β is expressed in the distal region of RVs, in the distal CSB, in the distal to proximal SSB, but it is absent in the most proximal region that will form the glomerulus. By E17.5, HNF1-β is present in all tubular epithelial cells of the mature nephrons but not in the glomeruli. MM: metanephric mesenchyme; UB: ureteric bud; WD: Wolffian duct; RV: renal vesicle; CSB: comma-shaped bodies; SSB: S-shaped bodies; D: distal; I: intermediate; P: proximal; DCT: distal convoluted tubule; PT: proximal tubulw; TAL: thick ascending limb of Henle; CD: collecting duct.

Figure 2. HNF-1β regulates the expression of solute transporters along the nephron

Defects in ion homeostasis reported in patients with HNF1B mutations include hypomagnesemia, hypokalemia, hyperuricemia, and rarely Fanconi syndrome. Whereas HNF-1α is restricted to the PT, HNF-1β is expressed in all epithelial cells of the nephron. HNF-1β target genes in the mature kidney encode OAT1/3/4, URAT1, NPT1, collectrin, uromodulin, NKCC2, the γ subunit of Na⁺-K⁺-ATPase, and FXR. Refer to the text for detailed information. PT: proximal tubule; TAL: thick ascending limb of Henle; DCT: distal convoluted tubule; CD: collecting duct; HNF-1α/β: hepatocyte nuclear factor-1α/β; OAT1/3/4: organic anion transporter 1/3/4; NPT1: Na⁺-Pi cotransporter 1; URAT1: urate anion exchanger 1; OA⁻: organic anion; UA: uric acid/urate; ROMK: renal outer medullary K⁺ channel; NKCC2: Na⁺-K⁺-Cl⁻ transporter; CaSR: calcium-sensing receptor; TRPM6: transient receptor potential melastatin 6; FXR: farnesoid X nuclear receptor.

Figure 3. Schematic model of the molecular mechanisms involved in the regulation of HNF-1β expression and activity

Control of HNF1-β expression and activity in the cell nucleus can occur at multiple levels: 1) HNF1B gene transcription; 2) HNF1B mRNA stability; 3) HNF1-β dimerization and interaction with regulatory proteins. EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; PCBD1: pterin-4 alpha-carbinolamine dehydratase; P: phosphorylation site.