Role of the Cation-chloride-cotransporters in Cardiovascular Disease

Abstract

The SLC12 family of cation-chloride-cotransporters (CCCs), comprising potassium chloride cotransporters (KCCs)-mediated Cl- extrusion relative to sodium chloride cotransporters (NKCCs)-mediated Cl- loading, play vital roles in cell volume regulation and ion homeostasis. These functions of the CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells along with their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promote the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings even suggest hypothalamic signalling as a key signalling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

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 – 15 ). Hypertension, a leading risk factor for myocardial infarction, stroke, and congestive heart failure, affects billions of individuals worldwide ( 16 ).…”

Transcriptomic and proteomic analysis of marine nematodeLitoditis marinaacclimated to different salinities

“…The increased abundance of potassium channel and potassium/chloride cotransporter genes was consistent with their general requirement mediating K + and Clefflux to defense against cell swelling under hypoosmotic (Strange, 2004;Hoffmann et al, 2009). Specifically, it has long been documented that the potassium/chloride cotransporters regulate a broad range of physiological processes, including cell volume regulation and ion homeostasis in many vertebrate cell types, and are among the most medically relevant ion transporters in human (Lauf and Theg, 1980;Adragna et al, 2004;Kahle et al, 2015;Meor Azlan and Zhang, 2020;Zimanyi et al, 2020). Moreover, EVM0007934/vha-5, EVM0008374/mca-1 and EVM0000094/twk-33, were also demonstrated specific induction upon hyposaline stress in our previous report (Xie et al, 2021) (Table 1 and Supplementary Table 5), we therefore proposed that these above-mentioned ion transport related genes play crucial roles in both osmotic stress response and long-term acclimation processes specifically under low salinity condition in L. marina.…”

“…In multicellular organisms with more complicated structures, osmoregulation is conducted mainly by osmoregulatory tissues and organs, for instance, gill in crustacean and fish, kidney in mammals, which are even regulated by their neuroendocrine systems (Sinke and Deen, 2011;Kültz, 2012;Thabet et al, 2017;Niu et al, 2020;Pool et al, 2020;Vij et al, 2020). Moreover, disruption of important members in osmoregulatory process are reported contributing to diverse human diseases (Wilson et al, 2001;Sinke and Deen, 2011;Meor Azlan and Zhang, 2020;Silverman et al, 2020;Li et al, 2021). However, the precise mechanisms of osmotic sensation, signal transduction and adaptation remain poorly defined in invertebrate animals.…”