The purpose of this study was to determine whether leptin influences renal function. Increasing doses (0.3, 1, 3, 10, and 30 microg/min; 30 min per dose) of human leptin (h-leptin) infused into the renal artery of anesthetized rats caused a twofold increase (P < 0.01) in urine volume (UV), sodium excretion rate (U(Na)V), and the ratio of U(Na)V to potassium excretion rate (U(K)V) from the ipsilateral kidney but had no effect on arterial blood pressure, renal blood flow, glomerular filtration rate, or U(K)V. Mouse leptin was inactive in the rat. In a second study, a single dose of h-leptin (30 microg/min) infused into the renal artery caused a significant twofold increase in UV and U(Na)V from the ipsilateral but not contralateral kidney and revealed a time lag (approximately 1.5 h) in the measurable response. In a third study, single doses of h-leptin were infused into the renal artery of four groups of rats (0.3, 1, 3, and 10 microg/min) for 140 min. The ratio of U(Na)V to U(K)V from the ipsilateral kidney was significantly increased by all doses of h-leptin. We conclude that h-leptin may function as a potassium-sparing diuretic/natriuretic factor.