1. Novel mechanism of salt-induced glomerular injury: critical role of eNOS and angiotensin II.
- Author
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Nakamura T, Kataoka K, Tokutomi Y, Nako H, Toyama K, Dong YF, Koibuchi N, Yamamoto E, Yasuda O, Ogawa H, and Kim-Mitsuyama S
- Subjects
- Albuminuria physiopathology, Angiotensin II Type 1 Receptor Blockers pharmacology, Angiotensin II Type 1 Receptor Blockers therapeutic use, Animals, Antioxidants pharmacology, Antioxidants therapeutic use, Biphenyl Compounds pharmacology, Biphenyl Compounds therapeutic use, Blood Pressure drug effects, Cyclic N-Oxides pharmacology, Cyclic N-Oxides therapeutic use, Disease Models, Animal, Glomerulonephritis prevention & control, Irbesartan, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type III deficiency, Nitric Oxide Synthase Type III genetics, Oxidative Stress drug effects, Sodium Chloride, Dietary pharmacology, Spin Labels, Tetrazoles pharmacology, Tetrazoles therapeutic use, Angiotensin II physiology, Glomerulonephritis chemically induced, Glomerulonephritis physiopathology, Nitric Oxide Synthase Type III physiology, Oxidative Stress physiology, Sodium Chloride, Dietary adverse effects
- Abstract
Objectives: The present study was undertaken to examine the role of endothelial nitric oxide synthase (eNOS) in salt-sensitive renal injury., Methods: The effects of high-salt diet on renal injury were compared between wild-type and eNOS-/- mice. To examine the role of glomerular angiotensin II and oxidative stress, high-salt fed eNOS-/- mice were given irbesartan, an angiotensin receptor blocker, or tempol, an antioxidant., Results: Four weeks of high-salt diet in wild-type mice, which rapidly caused glomerular eNOS activation and subsequent increase in nitric oxide, did not at all induce renal injury, indicating that wild-type mice are salt-resistant. On the contrary, high-salt diet in eNOS-/- mice, which little increased nitric oxide, rapidly increased urinary albumin excretion, followed by glomerular macrophage infiltration and glomerular sclerosis. Thus, eNOS deficiency caused salt-sensitive glomerular injury. Salt-induced glomerular injury in eNOS-/- mice was preceded by rapid enhancement of glomerular superoxide followed by enhancement of glomerular endothelial angiotensinogen and angiotensin II. Irbesartan and tempol, independently of blood pressure, markedly prevented salt-induced glomerular injury in eNOS-/- mice, and these protective effects were attributed to the attenuation of glomerular oxidative stress and glomerular angiotensinogen-derived angiotensin II., Conclusion: We propose that eNOS dysfunction plays a causative role in salt-induced glomerular injury, through augmentation of glomerular oxidative stress-induced angiotensinogen.
- Published
- 2011
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