The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney

被引:11
作者
Anderegg, Manuel A. [1 ,2 ,3 ]
Albano, Giuseppe [1 ,2 ,3 ]
Hanke, Daniela [1 ,2 ,3 ]
Deisl, Christine [1 ,2 ,3 ]
Uehlinger, Dominik E. [1 ]
Brandt, Simone [4 ]
Bhardwaj, Rajesh [1 ,2 ,3 ]
Hediger, Matthias A. [1 ,2 ,3 ]
Fuster, Daniel G. [1 ,2 ,3 ,5 ]
机构
[1] Univ Bern, Bern Univ Hosp, Dept Nephrol & Hypertens, Inselspital, Freiburgstr 15, CH-3010 Bern, Switzerland
[2] Univ Bern, Swiss Natl Ctr Competence Res TransCure, Bern, Switzerland
[3] Univ Bern, Dept Biomed Res, Bern, Switzerland
[4] Univ Zurich, Univ Hosp Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland
[5] Univ Zurich, Swiss Natl Ctr Competence Res KidneyCH, Zurich, Switzerland
基金
瑞士国家科学基金会;
关键词
blood pressure; KLHL3; NCC; NHA2; sodium/hydrogen exchanger; thiazide; ubiquitylation; urine calcium; WNK4; SODIUM-LITHIUM COUNTERTRANSPORT; NA+-CL-COTRANSPORTER; KELCH-LIKE; 3; PSEUDOHYPOALDOSTERONISM TYPE-II; DISTAL CONVOLUTED TUBULE; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; TRANSCELLULAR CALCIUM; EVOLUTIONARY ORIGINS; MICE LACKING; RENAL NA+;
D O I
10.1016/j.kint.2020.08.023
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but the role of NHA2 in kidney function and blood pressure homeostasis is currently unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure, normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were significantly reduced in the kidneys of NHA2 knockout mice. In vitro experiments recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4 stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3). More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation. Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC pathway and is a novel regulator of blood pressure homeostasis in the kidney.
引用
收藏
页码:350 / 363
页数:14
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