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

Abstract

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.

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

“…NCC is known to be regulated at the transcriptional and also at the posttranslational level, through phosphorylation, ubiquitination, and glycosylation by the renin-angiotensin system, K + , kinases, and hormones [45,46]. Aldosterone regulation of NCC expression and activity is consistent with the expression of 11βHSD2 at the DCT segment [35,36].…”

Cryo-EM structure of the human sodium-chloride cotransporter NCC

“…Malfunction of NCC leads to renal Na + waste and hypotension, causing Gitelman syndrome, a widely reported inherited kidney disease, depicted by metabolic alkalosis and hypokalemia, along with urinary calcium, hypocalcemia, and hypomagnesaemia (5,12). Increased NCC activity leads to familial hyperkalemic hypertension (13)(14)(15). Hypertension, a leading risk factor for myocardial infarction, stroke, and congestive heart failure, affects billions of individuals worldwide (16).…”

Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

“…The renal system plays a critical role in blood pressure homeostasis. Water retention in the kidney, due to increased sodium reabsorption, causes extracellular fluid (ECF) volume expansion [4]. The volume expansion contributes to the elevation of preload which contributes to the increase in blood pressure.…”