title: Novel mechanism of salt-induced glomerular injury: critical role of eNOS and angiotensin II.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  We propose that eNOS dysfunction plays a causative role in salt-induced glomerular injury, through augmentation of glomerular oxidative stress-induced angiotensinogen.
authors: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors: Taishi
authors: T
authors: Nakamura
authors: Keiichiro
authors: K
authors: Kataoka
authors: Yoshiko
authors: Y
authors: Tokutomi
authors: Hisato
authors: H
authors: Nako
authors: Kensuke
authors: K
authors: Toyama
authors: Yi-Fei
authors: YF
authors: Dong
authors: Nobutaka
authors: N
authors: Koibuchi
authors: Eiichiro
authors: E
authors: Yamamoto
authors: Osamu
authors: O
authors: Yasuda
authors: Hisao
authors: H
authors: Ogawa
authors: Shokei
authors: S
authors: Kim-Mitsuyama
mesh_terms: D000419:Albuminuria / Q000503:physiopathology; D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects* / Q000494:pharmacology; D013113:Spin Labels; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D013777:Tetrazoles; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000077405:Irbesartan; C001803:tempol