Abstract MP44: Proteolytic Activation Of ENaC Mediates Fructose-Induced Salt-Sensitive Hypertension

Abstract

In nephrotic syndrome, glomerular injury leads to filtration of plasma proteases. Once in the urine, these enzymes cleave and activate the epithelial Na channel (ENaC) causing inappropriate Na retention and hypertension. Dietary fructose causes inappropriate Na retention and salt-sensitive hypertension but whether proteolytic activation of ENaC is involved, and the source of the proteases, is unknown. We hypothesized that dietary fructose increases expression and release of proteases from the proximal nephron, and that these enzymes activate ENaC thereby causing Na retention and salt-sensitive hypertension. To test this hypothesis we first measured proximal nephron protease expression and urinary protease excretion in rats on either a high-salt diet without fructose (high salt) or one containing 4% NaCl plus 20% fructose in the drinking water (high salt/fructose) for 7 days. High salt/fructose treatment increased proximal nephron expression of trypsin I, an enzyme known to cleave and activate ENaC, by 68±7% (p < 0.01). Urinary excretion of trypsin I was 8.4±1.3 arbitrary units/μg protein in rats fed high salt while it was 20.3±4.6 arbitrary units/μg protein in those on the high salt/fructose diet, 142% greater (p < 0.02). There was no difference in total urinary protein excretion between groups. Finally, we examined the effect of high salt/fructose and high salt plus 20% glucose) high salt/glucose) on blood pressure before and after oral amiloride. After 7 days the systolic blood pressure of rats on high salt/fructose was 148±6 mm Hg while it was only 124±5 in those on high salt/glucose (p < 0.02). Amiloride reduced systolic blood pressure in rats on the high salt/fructose diet from 148±6 to 134±5 mm Hg but had no significant effect on the high salt/glucose group. We conclude that proteolytic cleavage of ENaC contributes to fructose-induced salt-sensitive hypertension and that the source of the protease(s) is likely the proximal tubule rather than glomerular filtration.