Direct Evidence for Intrarenal Chymase-dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Overview

Journal Hypertension

Date 2012 Dec 6

PMID 23213190

Citations 19

Authors

Sungmi Park

Benjamin J Bivona

Stephen M Ford Jr

Sen Xu

Hiroyuki Kobori

Lawrence de Garavilla

Lisa M Harrison-Bernard

Affiliations

Soon will be listed here.

Abstract

Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type 2 diabetes mellitus. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes mellitus. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro(10)]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared with control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro(11), D-Ala(12)]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared with control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3, and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro(11), D-Ala(12)]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro(11), D-Ala(12)]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mouse mast cell protease-4 or chymase/β-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/β-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared with control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute to the progression of diabetic kidney disease.

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