| First Author | Kompatscher A | Year | 2018 |
| Journal | Am J Physiol Renal Physiol | Volume | 315 |
| Issue | 1 | Pages | F27-F35 |
| PubMed ID | 29561186 | Mgi Jnum | J:280666 |
| Mgi Id | MGI:6368969 | Doi | 10.1152/ajprenal.00601.2017 |
| Citation | Kompatscher A, et al. (2018) Transcription factor HNF1beta regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney. Am J Physiol Renal Physiol 315(1):F27-F35 |
| abstractText | Mutations in hepatocyte nuclear factor 1beta (HNF1beta) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1beta), 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 HNF1beta research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1beta electrolyte phenotype, although 70% of Mg(2+) is reabsorbed in the thick ascending limb of Henle's loop (TAL). An important regulator of Mg(2+) reabsorption in the TAL is the calcium-sensing receptor (CaSR). This study used several methods to elucidate the role of HNF1beta in electrolyte reabsorption in the TAL. HNF1beta ChIP-seq data revealed a conserved HNF1beta binding site in the second intron of the CaSR gene. Luciferase-promoter assays displayed a 5.8-fold increase in CaSR expression when HNF1beta was present. Expression of the HNF1beta p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1beta 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 kidney-specific HNF1beta 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, HNF1beta is a transcriptional activator of the CaSR. Consequently, patients with HNF1beta mutations may have reduced CaSR activity in the kidney, which could explain cyst progression and hyperabsorption of Ca(2+) and Mg(2+) in the TAL resulting in hypocalciuria. |
