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
2018 AJP - Renal Physiology  
Kompatscher A, de Baaij JH, Aboudehen K, Farahani S, van Son LH, Milatz S, Himmerkus N, Veenstra GC, Bindels RJ, Hoenderop JG. Transcription factor HNF1␤ regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney. tions in hepatocyte nuclear factor 1␤ (HNF1␤) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1␤), and patients tend to develop renal cysts, maturity-onset diabetes of the young (MODY), and suffer from electrolyte disturbances,
more » ... ncluding hypomagnesemia, hypokalemia, and hypocalciuria. Previous HNF1␤ research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1␤ electrolyte phenotype, although 70% of Mg 2ϩ is reabsorbed in the thick ascending limb of Henle's loop (TAL). An important regulator of Mg 2ϩ reabsorption in the TAL is the calcium-sensing receptor (CaSR). This study used several methods to elucidate the role of HNF1␤ in electrolyte reabsorption in the TAL. HNF1␤ ChIP-seq data revealed a conserved HNF1␤ binding site in the second intron of the CaSR gene. Luciferasepromoter assays displayed a 5.8-fold increase in CaSR expression when HNF1␤ was present. Expression of the HNF1␤ p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1␤ 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 HNF1␤ 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, HNF1␤ is a transcriptional activator of the CaSR. Consequently, patients with HNF1␤ mutations may have reduced CaSR activity in the kidney, which could explain cyst progression and hyperabsorption of Ca 2ϩ and Mg 2ϩ in the TAL resulting in hypocalciuria. calcium-sensing receptor; hepatocyte nuclear factor 1␤; hypomagnesemia; kidney; thick ascending limb of Henle
doi:10.1152/ajprenal.00601.2017 pmid:29561186 fatcat:6u5xfqtfordipfkqz7ztcxyd4i