A Role of Intestine in Hypertension: Mechanism of Suppression of Intestinal Na-H Exchanger Isoform-3 in Spontaneously Hypertensive Rats

Abstract

The main objective of this study was to investigate the role and the underlying mechanism of Na-H exchanger-3 (NHE-3) expression in spontaneously hypertensive rat (SHR) intestine. Expression of colonic and ileal NHE-3 isoform, its regulatory factor-1 (NHERF-1) and cyclic GMP kinase II (cGKII) were examined using western blot analysis. Since NHE-3 activity is regulated by its abundance on the plasma membrane, its levels were also examined in lipid rafts-enriched membrane fractions. The lipid rafts fractions were characterized by examining the concentration of flotillin-1 and caveolin-1, total protein, and cholesterol. Twelve-weeks-old SHR used in this study developed significant hypertension, proteinuria, and renal and cardiac hypertrophy. These changes were significantly reversed by captopril treatment. There was a significant decrease in the levels of NHE-3 and NHERF-1 proteins, and sodium pump activity, but an increase in the cGKII levels in both tissues from SHR. Reduction in NHERF-1 levels was reversed by captopril but not of the other proteins. Cholesterol profile was significantly different in SHR colon as compared to normo-tensive Wistar Kyoto rats. These findings suggest that suppression of NHE-3 in intestine is a counteracting mechanism of hypertension and is regulated by NHERF-1 through cGKII activation in SHR. NHE-3 suppression together with decrease in the sodium pump activity would accumulate intracellular Na+ and may contribute to the reported hypertension-induced tissue damage in the GI-tract.