Transcription factor HNF1β regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney

Andreas Kompatscher, Jeroen H.F. De Baaij, Karam Aboudehen, Shayan Farahani, Lex H.J. Van Son, Susanne Milatz, Nina Himmerkus, Gertjan C. Veenstra, René J.M. Bindels, Joost G.J. Hoenderop

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5 Scopus citations

Abstract

Mutations in hepatocyte nuclear factor 1β (HNF1β) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1β), and patients tend to develop renal cysts, maturity-onset diabetes of the young (MODY), and suffer from electrolyte disturbances, including hypomagnesemia, hypokalemia, and hypocalciuria. Previous HNF1β research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1β electrolyte phenotype, although 70% of Mg2+ is reabsorbed in the thick ascending limb of Henle’s loop (TAL). An important regulator of Mg2+ reabsorption in the TAL is the calcium-sensing receptor (CaSR). This study used several methods to elucidate the role of HNF1β in electrolyte reabsorption in the TAL. HNF1β ChIP-seq data revealed a conserved HNF1β binding site in the second intron of the CaSR gene. Luciferasepromoter assays displayed a 5.8-fold increase in CaSR expression when HNF1β was present. Expression of the HNF1β p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1β knockdown in an immortalized mouse kidney TAL cell line (MKTAL) reduced expression of the CaSR and Cldn14 (claudin 14) by 56% and 48%, respectively, while Cldn10b expression was upregulated 5.0-fold. These results were confirmed in a kidneyspecific HNF1β knockout mouse, which exhibited downregulation of the Casr by 81%. Cldn19 and Cldn10b expression levels were also decreased by 37% and 83%, respectively, whereas Cldn3 was upregulated by 4.6-fold. In conclusion, HNF1β is a transcriptional activator of the CaSR. Consequently, patients with HNF1β mutations may have reduced CaSR activity in the kidney, which could explain cyst progression and hyperabsorption of Ca2+ and Mg2+ in the TAL resulting in hypocalciuria.

Original languageEnglish (US)
Pages (from-to)F27-F35
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number1
DOIs
StatePublished - Jul 2018

Bibliographical note

Funding Information:
This work was supported by grants from the Netherlands Organization for Scientific Research (NWO VICI 016.130.668). Dr. Jeroen de Baaij is supported by a grant from NWO (Veni 016.186.012) and the Dutch Kidney Foundation (Kolff 14OKG17).

Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.

Keywords

  • Calcium-sensing receptor
  • Hepatocyte nuclear factor 1β
  • Hypomagnesemia
  • Kidney
  • Thick ascending limb of henle

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