Transcription factor HNF1ß regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney.
Am J Physiol Renal Physiol
; 315(1): F27-F35, 2018 07 01.
Article
en En
| MEDLINE
| ID: mdl-29561186
ABSTRACT
Mutations in hepatocyte nuclear factor 1ß (HNF1ß) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1ß), 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 HNF1ß research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1ß 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 HNF1ß in electrolyte reabsorption in the TAL. HNF1ß ChIP-seq data revealed a conserved HNF1ß binding site in the second intron of the CaSR gene. Luciferase-promoter assays displayed a 5.8-fold increase in CaSR expression when HNF1ß was present. Expression of the HNF1ß p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1ß 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 HNF1ß 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, HNF1ß is a transcriptional activator of the CaSR. Consequently, patients with HNF1ß 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Acoplados a Proteínas G
/
Factor Nuclear 1-beta del Hepatocito
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Asa de la Nefrona
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Physiol Renal Physiol
Asunto de la revista:
FISIOLOGIA
/
NEFROLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Países Bajos