679 INHIBITION OF CHYMASE-DEPENDENT PRODUCTION OF KIDNEY ANGIOTENSIN II IMPROVES RENAL SODIUM HANDLING AND PREVENTS ASCITES IN EXPERIMENTAL LIVER CIRRHOSIS

Abstract

Non-ACE-dependent renal and cardiac production of angiotensin II (AngioII) involves the conversion of angiotensin I into Angio II by chymase (a cell protease). This accounts for 75% of heart and kidney AngioII content. In liver cirrhosis, AngioII is known to cause renal vasoconstriction and sodium retention but renal chymase function is still unknown. In order to assess the kidney content, localization and function of chymase in advanced liver cirrhosis, five groups of 10 rats were studied: controls (group G1), controls receiving 10 mg/kg b.w. of an oral chymase inhibitor (SF2809E) three times a week for 9 weeks (G2), rats with cirrhosis induced by 13 weeks of oral CCl4 (G3), rats receiving CCl4 for the above period of time (13 weeks) but receiving also 10 or 20 mg/kg b.w. SF2809E three times a week between the 4th and 13th weeks of CCl4 administration (G4 and G5). All rats were then submitted to evaluation of renal function, hormonal status, kidney content of chymase and Angio II, and kidney immunolocalization of chymase (indirect immunofluorescence staining). Rats belonging to G3 had sodium retention and ascites. Rats belonging to G5 were devoid of ascites; renal tissue content of AngioII, plasma renin activity, plasma norepinephrine and vasopressin (ADH) levels were lower in G5 than in G3 rats (all P<0.03). Glomerular filtration rate (inulin clearance), filtration fraction (the fraction of renal plasma flow that undergoes glomerular filtration), urine flow, free water clearance, and urinary sodium excretion were higher in G5 than in G3 rats (all P<0.01). Renal protein content of chymase was higher in cirrhotic than in normal rats (P<0.03). In kidneys of cirrhotic rats belonging to G3, chymase was detected in cortical arterioles and proximal tubules. In rats with advanced liver cirrhosis, chronic inhibition of renal chymase improves renal sodium and water handling through a tubular diuretic effect which in turn is associated with better glomerular perfusion and filtration.