Kidney damage after renal ablation is worsened in endothelial nitric oxide synthase -/- mice and improved by combined administration of L-arginine and antioxidants.
OBJECTIVE
Reduction in nitric oxide (NO) levels during kidney failure has been related to the reaction of NO with superoxide anions to yield peroxynitrite which possesses the biological activity responsible for renal damage. However, stimulation of the NO pathway ameliorates the progression of kidney failure. Thus, it is unclear whether NO prevents or acts as the compound responsible for the cytotoxicity observed during kidney failure.


METHODS
We evaluated the development of kidney failure in animals that were wild type and deficient in endothelial NO synthase (eNOS -/-) and tested the effects of an antioxidant treatment and NO precursors on the generation of superoxide anion and kidney failure parameters.


RESULTS
In wild-type mice, five-sixths nephrectomy increased proteinuria from 3.0 +/- 0.35 to 14.5 +/- 0.76 mg protein/24 h (P < 0.05), blood pressure from 83.1 +/- 1.8 to 126.6 +/- 1.7 mmHg (P < 0.05), and superoxide production from 1.4 +/- 0.6% to 74.3 +/- 0.8% (P < 0.05). The effects of five-sixths nephrectomy on the eNOS -/- mice were greater compared with wild-type mice. Proteinuria increased from 6.7 +/- 0.5 to 22.7 +/- 2.0 mg protein/24 h (P < 0.05), blood pressure increased from 93.3 +/- 0.9 to 151.2 +/- 3.4 mmHg (P < 0.05), and superoxide production increased from 12.9 +/- 0.5% to 99.8 +/- 1.3% (P < 0.05). The nitrotyrosine levels were lower in eNOS -/- mice as compared to wild-type mice. A combination of L-arginine and antioxidant treatment ameliorated renal damage. The effect was improved in wild-type animals.


CONCLUSIONS
Our data support the relevance of NO as an antagonist to superoxide in renal tissues and suggest that the loss of this mechanism promotes the progression of kidney failure.
Mendoza
Monica G Arellano
MG
Escuela Superior de Medicina IPN, México City, Mexico.
Castillo-Henkel
Carlos
C
Medina-Santillan
Roberto
R
Jarillo Luna
R Adriana
RA
Robles
Hilda Vargas
HV
Romo
Eunice
E
Rios
Amelia
A
Escalante
Bruno
B
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure; D004195:Disease Models, Animal; D004338:Drug Combinations; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism* / Q000652:urine; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000975:Antioxidants; D004338:Drug Combinations; D013481:Superoxides; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse