Role of the alternative splice variant of NCC in blood pressure control

The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC(3)) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCC(SV)), in several (patho)physiological conditions. In the human kidney, NCC(SV) localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCC(SV) abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCC(SV), was shown to play an instrumental role in NCC(SV) as well as NCC(3) function. This review aims to summarize these new insights of NCC(SV) function in humans that broadens the understanding on NCC regulation in blood pressure control.