The hepatorenal reflex plays an important role in water and salt homeostasis by matching renal excretion to gastrointestinal absorption. This homeostatic mechanism is impaired in nephrotic rats. The present study tested the hypothesis that, in nephrotic rats, the renal sodium excretion response to hypertonic saline infusion is impaired due to decreased sensitivity of the hepatoportal sodium-sensing mechanism. The present study was performed in control and adriamycin (ADR)-induced nephrotic syndrome rats. After baseline data collection, urinary sodium (U NaV) and potassium (U KV) excretion responses were tested following continuous infusion of hypertonic NaCl solution (20 μL/min for 30 min) into either the femoral or mesenteric vein. A second series of experiments tested hepatic and renal nerve responses to continuous mesenteric vein infusion of hypertonic NaCl (10 μL/s for 30 s). Compared with control rats, nephrotic rats displayed significantly lower baseline U NaV and U KV excretion. In control rats, mesenteric compared with femoral vein infusion of hypertonic NaCl produced a more rapid and greater increase in U NaV. In contrast, in nephrotic rats, femoral and mesenteric vein infusion caused similar increases in U NaV and the maximum increases in U NaV to either route of infusion were much lower in nephrotic than control rats. Furthermore, portal hypertonic saline infusion caused greater increases in hepatic nerve activity and greater decreases in renal nerve activity in control compared with nephrotic rats. These data suggest that, in rats, adriamycin treatment decreases hepatoportal sodium-sensing sensitivity, leading to marked impairment of hepatorenal reflex responses, potentially contributing to salt and water retention. © 2012 Blackwell Publishing Asia Pty Ltd.