Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis

Daily dietary potassium (K) intake may be as large as the extracellular K pool. To avoid acute hyperkalemia, rapid removal of K from the extracellular space is essential. This is achieved by translocating K into cells and increasing urinary K excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K sensor that can modify sodium (Na) delivery to downstream segments to promote or limit K secretion. K sensing is mediated by the basolateral K channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K-induced aldosterone secretion, K sensing by renal epithelial cells represents a second feedback mechanism to control K balance. NCC's role in K homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na reabsorption while preventing K secretion. Conversely, NCC inactivation by high dietary K intake maximizes kaliuresis and limits Na retention, despite high aldosterone levels. NCC activation by a low-K diet contributes to salt-sensitive hypertension. K-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K diet. A possible role for K in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K homeostasis in health and disease.