Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure.
Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Nitric oxide (NO) has been shown to be increased in sepsis. Endothelial nitric oxide synthase (eNOS) is one of the major regulators of arterial blood pressure and regional blood flow; however, its in vivo role in septic ARF is still unclear. We hypothesized that eNOS affords a protective effect against the renal vasoconstriction during endotoxemia. Because there are no specific inhibitors for eNOS, the study was therefore undertaken in eNOS knockout mice. There was no significant difference in baseline glomerular filtration rate (GFR) between the wild-type mice and the eNOS knockout mice (140 +/- 10 vs. 157 +/- 18 microl/min, n = 9, P = not significant). However, renal blood flow (RBF) was significantly decreased in eNOS knockout mice compared with the wild-type controls (0.62 +/- 0.05 ml/min, n = 6 vs. 0.98 +/- 0.13 ml/min, n = 8, P < 0.05). Mean arterial pressure (MAP) was significantly higher in eNOS knockout mice than the wild-type controls (109 +/- 5 vs. 80 +/- 1 mmHg, n = 10, P < 0.01). Thus renal vascular resistance (RVR) was much higher in eNOS knockout mice than in the wild-type mice (176 +/- 2, n = 6 vs. 82 +/- 1 mmHg.ml(-1).min(-1), n = 8, P < 0.01). When 1.0 mg/kg LPS was injected, there was no change in MAP in either the wild-type (84 +/- 3 mmHg, n = 10) or the eNOS knockout mice (105 +/- 5 mmHg, n = 10). Although GFR (154 +/- 22 microl/min, n = 8) and RBF (1.19 +/- 0.05 ml/min, n = 9) remained unchanged with the 1.0-mg/kg dose of LPS in the wild-type mice, GFR (83 +/- 18 vs. 140 +/- 10 microl/min, n = 6, P < 0.01) and RBF (0.36 +/- 0.04 vs. 0.62 +/- 0.05 ml/min, n = 6, P < 0.01) decreased significantly in the eNOS knockout mice. Fractional excretion of sodium increased significantly in eNOS knockout mice during endotoxemia (3.61 +/- 0.78, n = 7 vs. 0.95 +/- 0.14, n = 6, P < 0.01), whereas it remained unchanged in the wild-type mice (0.59 +/- 0.16, n = 9 vs. 0.42 +/- 0.05, n = 6, P = not significant). In summary, eNOS knockout mice have increased RVR and are more susceptible to endotoxemic ARF than wild-type mice despite higher MAP.
Dept. of Medicine, Univ. of Colorado Health Sciences Center, 4200 East 9th Avenue, Box C-281, Denver, CO 80262, USA.
Wei
W
Wang
Amit
A
Mitra
Brian
B
Poole
Sandor
S
Falk
M Scott
MS
Lucia
Shalini
S
Tayal
Robert
R
Schrier
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004731:Endotoxins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000172:deficiency*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine
D004731:Endotoxins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D012964:Sodium; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse