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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Reviews
• 页码范围: 1117-1128
• 页数: 12页
• 语种: 英文

摘要

Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mor-tality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hyperten-sion 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 convo-luted 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 un-covered 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 regu-lator 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 down-stream 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 summa-rizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeu-tic targets for treating hypertension.