Abstract P209: Activation of Renal (Pro)Renin Receptor Contributes to High Fuctose-induced Salt Sensitivity

Abstract

A high-fructose (HF) diet is shown to induce salt-sensitive hypertension but the underlying mechanism remains unclear. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. Male Sprague-Dawley rats were randomly divided into the following 4 groups: 1) Control, 2) Fructose, 3) Fructose + PRO20, and 4) Fructose + allopurinol, and the treatments lasted for 3 months. Fructose was added to drinking water (as 20% solution) so was allopurinol (at 30 mg/kg/d). PRO20, an antagonist of (pro)renin receptor, was administered at 700 μg/kg/day via i.p. injections. High fructose (HF) intake induced a 150% increase in renal protein expression of full-length PRR (fPRR), which were attenuated by allopurinol. HF intake also upregulated renal mRNA and protein expression of NHE3 (206% for protein) and NKCC2 (169% for protein) as well as in vivo NKCC2 activity (2-fold increases in 1-h urine volume and UNaV), all of which were nearly completely blocked by PRO20 or allopurinol treatment. HF intake induced >5-fold increases in urinary renin activity, renin content, and total renin content, and a 2-fold increase in urinary AngII, which were suppressed by 60-70% with PRO20 or allopurinol, contrasting to relatively consistent values of these parameters in the plasma, evidence of involvement of intrarenal RAS . At the last week of the experimental period, radiotelemetry was performed to monitor blood pressure during one-week high salt (HS) diet (8% NaCl). The 3-mo HF intake or a 1-wk HS diet alone did not affect mean arterial pressure (MAP), but the combination of the two maneuvers induced a ~10 mm Hg increase of MAP, which was abolished by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid (UA) increased protein expression of soluble PRR (sPRR) in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via UA stimulates renal expression of PRR/sPRR that stimulate NHE3 and NKCC2 expression and intrarenal RAS to induce salt-sensitive hypertension.