Recent studies suggest that high fructose (HF) diet induces salt-sensitive hypertension but the underlying mechanism largely remains elusive.We hypothesize that renal (pro)renin receptor (PRR) may play a role in HF-induced salt-sensitive hypertension through an influence on sodium reabsorption.In cultured human kidney 2 (HK2) cells, 5 mmol/L fructose increased protein expression of full-length PRR (fPRR) and soluble PRR (sPRR) and medium sPRR secretion in time-and dose-dependent manner, which were inhibited by allopurinol pretreatment.In Sprague-Dawley rats, HF intake increased renal fPRR and sPRR expression, urinary excretion of sPRR, and the concentration of plasma sPRR.HF increased renal ACE, AT1R, and AT2R mRNA expression, and upregulatedNKCC2, NHE3, and ENaC expression at both protein and mRNA levels, all of which were blunted by an PRR decoy inhibitor PRO20.The in vivo NKCC2 activity as reflected by the rapid diuresis and natriuretic responses to furosemide was elevated by high fructose feeding which was completely blocked by PRO20 treatment.By radiotelemetry, fructose feeding or high salt diet alone did not affect mean arterial pressure (MAP), but the combination of the two maneuvers elevated MAP about 10 mmHg, which was blunted by PRO20 treatment.Following HF, kidney and urinary but not plasma renin and angiotensin Ⅱ were upregulated, which was blunted by PRO20.Taken together, our data suggests that fructose stimulates renal PRR expression that stimulates NKCC2 expression that drives salt-sensitive hypertension.