Hypokalemia is a prominent feature of Gitelman syndrome and a common side effect of thiazide use in the treatment of hypertension. It is widely recognized that genetic or pharmacological inhibition of the renal thiazide-sensitive sodium chloride cotransporter (NCC) initiates the potentially severe renal potassium loss observed in these settings. Surprisingly, hypokalemia has not been detected in NCC (-/-) mice (Schultheis, P. J., Lorenz, J. N., Meneton, P., Nieman, M. L., Riddle, T. M., Flagella, M., Duffy, J. J., Doetschman, T., Miller, M. L. & Shull, G. E. (1998) J. Biol. Chem. 273, 29150-29155.) maintained on normal rodent diets. We now show that modest reduction of dietary potassium induced a marked reduction in plasma potassium and elevated renal potassium excretion in NCC (-/-) mice, which was associated with a pronounced polydipsia and polyuria of central origin. These findings are consistent with the development of potassium depletion in NCC (-/-) mice and were not seen in wild-type mice maintained on the same low potassium diet. In addition, plasma aldosterone levels were significantly elevated in NCC (-/-) mice even in the presence of a low potassium diet. Collectively, these findings suggest an early central component to the polyuria of Gitelman syndrome and show that both elevated aldosterone and dietary potassium content contribute to the development of hypokalemia in Gitelman syndrome. Therefore, NCC (-/-) mice are more sensitive to reductions in dietary potassium than wild-type mice and become hypokalemic thus more faithfully representing the Gitelman phenotype seen in humans.