Pathophysiological role of Na–Cl cotransporter in kidneys, blood pressure, and metabolism

The Na–Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na⁺ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na⁺ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC’s novel role in immune and metabolic regulation.