title: Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice.
abstract: Randomized clinical trials have clearly shown that inhibition of the renin-angiotensin system (RAS) will slow the rate of progression of diabetic nephropathy, but controversy remains about whether the observed beneficial effects result from more than control of blood pressure. Deletion of eNOS in a model of type II diabetes, db/db mice (eNOS(-/-) db/db), induces an accelerated nephropathy and provides an excellent model of human diabetic nephropathy. As is frequently seen in type II diabetes, blood pressure is moderately elevated in eNOS(-/-) db/db mice. To determine the role of elevated blood pressure per se vs. additional deleterious effects of the RAS in mediation of disease progression, 8-wk-old eNOS(-/-) db/db mice were randomly divided into three groups: vehicle, treatment with the angiotensin-converting enzyme inhibitor (ACEI) captopril, or treatment with "triple therapy" (hydralazine, resperine, hydrocholorothiazide), and the animals were euthanized after treatment for 12 wk. Blood pressure was reduced to comparable levels with ACE inhibition or triple therapy. Although both treatment regimens decreased development of diabetic nephropathy, ACE inhibition led to more profound reductions in albuminuria, glomerulosclerosis, markers of tubulointerstitial injury, macrophage infiltration, and markers of inflammation. Therefore, this animal model suggests that while there is an important role for blood pressure control, RAS blockade provides additional benefits in slowing the progression of diabetic nephropathy.
authors: Div. of Nephrology, C3121 MCN, Vanderbilt Univ. School of Medicine and Nashville Veterans Affairs Hospital, Nashville, TN 37232, USA.
authors: Ming-Zhi
authors: MZ
authors: Zhang
authors: Suwan
authors: S
authors: Wang
authors: Shilin
authors: S
authors: Yang
authors: Haichun
authors: H
authors: Yang
authors: Xiaofeng
authors: X
authors: Fan
authors: Takamune
authors: T
authors: Takahashi
authors: Raymond C
authors: RC
authors: Harris
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D006852:Hydrochlorothiazide; D006830:Hydralazine; D012110:Reserpine; D002216:Captopril; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse