SLC12A3 encodes the thiazide-sensitive sodium-chloride cotransporter (NCC), which serves as a key mediator of electroneutral sodium and chloride reabsorption in the kidney's distal convoluted tubules 123. The transporter functions through cotransport of Na+ and Cl- ions, maintaining electrolyte homeostasis and blood pressure regulation. Mechanistically, mutations in SLC12A3 can affect NCC function through multiple pathways: class 2 mutations eliminate transport activity, class 3 mutations impair protein trafficking to the plasma membrane, and class 4 mutations affect regulation or ion affinity while maintaining membrane localization 3. Recent research has revealed an additional function where SLC12A3 acts as a receptor for IL-18, triggering metabolic reprogramming in intestinal macrophages by promoting sodium influx and activating the STING pathway, leading to fatty acid oxidation and immune tolerance 4. Disease-wise, SLC12A3 mutations cause Gitelman syndrome, an autosomal recessive salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria 12. Over 500 mutations have been identified, with missense mutations comprising approximately 59-72% of cases in various populations 15. The Arg913Gln variant shows association with diabetic nephropathy in type 2 diabetes patients 6.