Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB.
BACKGROUND
Angiotensin II (Ang II) can up-regulate nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, whose product superoxide anion (O2-) can interact with nitric oxide (NO) to form peroxynitrite (ONOO-). We tested the hypothesis that Ang II subtype 1 (AT1) receptor activation enhances oxidative stress and nitrotyrosine deposition in the kidneys of rats with diabetes mellitus (DM).


METHODS
After two weeks of streptozotocin-induced DM, rats received either no treatment, an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) for two weeks. At four weeks, renal expression of the p47phox component of NAD(P)H oxidase, endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and nitrotyrosine were evaluated by Western blot and immunohistochemistry and related to plasma lipid peroxidation products (LPO), hydrogen peroxide production in the kidney and 24-hour protein excretion.


RESULTS
Immunoreactive expression of p47phox and eNOS were increased in DM with an increase in plasma LPO, renal hydrogen peroxide production and nitrotyrosine deposition. Expression of nNOS was unaltered. Treatment with either ACEI or ARB prevented all these findings and also prevented significant microalbuminuria. The treatments did not affect the elevated blood sugar, nor did DM or its treatment affect the blood pressure or the creatinine clearance.


CONCLUSIONS
Early proteinuric diabetic nephropathy increases renal expression of the p47phox component of NAD(P)H oxidase and eNOS with increased indices of systemic and renal oxidative/nitrosative stress. An ACEI or an ARB prevents these changes and prevents the development of proteinuria, independent of blood pressure or blood sugar. This finding indicates a pathogenic role for AT1 receptors in the development of oxidative damage in the kidneys during early DM.
Onozato
Maristela Lika
ML
Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
Tojo
Akihiro
A
Goto
Atsuo
A
Fujita
Toshiro
T
Wilcox
Christopher S
CS
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007546:Isoquinolines; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000077583:Quinapril; C081643:candesartan