title: Direct evidence for intrarenal chymase-dependent angiotensin II formation on the diabetic renal microvasculature.
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.
authors.affiliation: Department of Physiology, Box P7-3, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Bivona
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ford
authors.forename: Sen
authors.initials: S
authors.lastname: Xu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Harrison-Bernard
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D053818:Chymases / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D053818:Chymases; C081643:candesartan