Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension  

作　　者：Nur Farah Meor Azlan Maarten P.Koeners Jinwei Zhang 

机构地区：[1]Institute of Biomedical and Clinical Sciences,Medical School,College of Medicine and Health,University of Exeter,Hatherly Laboratories,Exeter EX44PS,UK

出　　处：《Acta Pharmaceutica Sinica B》2021年第5期1117-1128,共12页药学学报（英文版）

基　　金：supported by the University of Exeter Medical School(UK);NIH Grants R01 NS109358(USA)。

摘　　要：Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mortality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hypertension cannot be attributed to a single identifiable etiology.Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling,particularly the distal convoluted tubule(DCT)-native,thiazide-sensitive Na-Cl cotransporter(NCC).Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon’s and Gitelman syndromes respectively.Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC.In particular,NCC activity is controlled by phosphorylation/dephosphorylation,and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination.Studies have even found parvalbumin to be an unexpected regulator of the NCC.In recent years,there have been considerable advances in our understanding of NCC control mechanisms,particularly via the pathway containing the with-no-lysine[K](WNK)and its downstream target kinases,SPS/Ste20-related proline-alanine-rich kinase(SPAK)and oxidative stress responsive 1(OSR1),which has led to the discovery of novel inhibitory molecules.This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.

关 键 词：NaCl-cotransporter NCC Cardiovascular disease CUL3/KLHL3-WNK-SPAK/OSR1 Blood pressure regulation Kinase inhibitors Membrane trafficking Therapeutic targets HYPERTENSION 

分 类 号：R544.1[医药卫生—心血管疾病]