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.