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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 61; no. 2; pp. 465 - 471
• Main Authors: Park, Sungmi, Bivona, Benjamin J, Ford, Stephen M, Xu, Sen, Kobori, Hiroyuki, de Garavilla, Lawrence, Harrison-Bernard, Lisa M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.02.2013; Lippincott Williams & Wilkins
• Subjects: Angiotensin II - biosynthesis; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Arterial hypertension. Arterial hypotension; Benzimidazoles - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chymases - metabolism; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Diabetes Mellitus, Type 2 - metabolism; Kidney - blood supply; Kidney - drug effects; Kidney - metabolism; Male; Medical sciences; Mice; Microvessels - drug effects; Microvessels - metabolism; Peptidyl-Dipeptidase A - metabolism; Tetrazoles - pharmacology; Endocrinopathy; juxtamedullary nephron; Peptide hormone; Cardiovascular disease; Octapeptide; chymase inhibitor; JNJ-18054478; Angiotensin II; angiotensin-converting enzyme; db/db mouse; Hypertension; Serine endopeptidases; Enzyme; Diabetes mellitus; Rodentia; Intrarenal; Chymase; Peptidases; Vertebrata; Mammalia; Mouse; Animal; Nephron; Hydrolases; afferent arteriole
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.111.202424

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]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, D-Ala]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, D-Ala]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro, D-Ala]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.