Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tubular apoptosis in Akita angiotensinogen-transgenic mice
Open Access
- 1 April 2012
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Renal Physiology
- Vol. 302 (7), F840-F852
- https://doi.org/10.1152/ajprenal.00340.2011
Abstract
We investigated the effects of dual renin-angiotensin system (RAS) blockade on angiotensin-converting enzyme-2 (Ace2) expression, hypertension, and renal proximal tubular cell (RPTC) apoptosis in type 1 diabetic Akita angiotensinogen (Agt)-transgenic (Tg) mice that specifically overexpress Agt in their RPTCs. Adult (11 wk old) male Akita and Akita Agt-Tg mice were treated with two RAS blockers (ANG II receptor type 1 blocker losartan, 30 mg·kg−1·day−1) and angiotensin-converting enzyme (ACE) inhibitor perindopril (4 mg·kg−1·day−1) in drinking water. Same-age non-Akita littermates and Agt-Tg mice served as controls. Blood pressure, blood glucose, and albuminuria were monitored weekly. The animals were euthanized at age 16 wk. The left kidneys were processed for immunohistochemistry and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess gene and protein expression. Urinary ANG II and ANG 1–7 were quantified by ELISA. RAS blockade normalized renal Ace2 expression and urinary ANG 1–7 levels (both of which were low in untreated Akita and Akita Agt-Tg), prevented hypertension, albuminuria, tubulointerstitial fibrosis and tubular apoptosis, and inhibited profibrotic and proapoptotic gene expression in RPTCs of Akita and Akita Agt-Tg mice compared with non-Akita controls. Our results demonstrate the effectiveness of RAS blockade in preventing intrarenal RAS activation, hypertension, and nephropathy progression in diabetes and support the important role of intrarenal Ace2 expression in modulating hypertension and renal injury in diabetes.Keywords
This publication has 46 references indexed in Scilit:
- Prevention of Angiotensin II–Mediated Renal Oxidative Stress, Inflammation, and Fibrosis by Angiotensin-Converting Enzyme 2Hypertension, 2011
- Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Converting Enzyme 2Hypertension, 2010
- Human Recombinant ACE2 Reduces the Progression of Diabetic NephropathyDiabetes, 2009
- Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 DiabetesThe New England Journal of Medicine, 2008
- Effects of Intensive Glucose Lowering in Type 2 DiabetesThe New England Journal of Medicine, 2008
- Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase PathwayThe American Journal of Pathology, 2008
- Overexpression of Angiotensinogen Increases Tubular Apoptosis in DiabetesJournal of the American Society of Nephrology, 2008
- Angiotensin-(1–7) and the renin–angiotensin systemCurrent Opinion in Nephrology and Hypertension, 2007
- Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptorsKidney International, 2005
- Multiple Metabolic Hits Converge on CD36 as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic NephropathyPLoS Medicine, 2005