Proteinuria is reduced by inhibition of inducible nitric oxide synthase in rat renal ischemia-reperfusion injury.
BACKGROUND
Ischemia-reperfusion (IR)-induced nephrotoxicity is associated with proteinuria. There are reports on the involvement of inducible nitric oxide synthase (iNOS) in proteinuria in conjunction with renal disease. This study was designed to investigate the effect of N6-(1-iminoethyl)-L-lysine hydrochloride (L-Nil), a selective inhibitor of iNOS, to prevent proteinuria in IR injury.


METHODS
Ischemia was induced by 40-minute clamping of the renal arteries followed by 6-hour reperfusion. Rats were administered either L-Nil (3 mg/kg intravenous bolus followed by infusion of 1 mg/kg/h) or saline. To monitor glomerular and tubular functional changes before and after treatment, we measured blood urea nitrogen, plasma creatinine, and urinary N-acetyl-beta-D-glucosaminidase activity. Total protein (TP), albumin, and low- (LMW) and high-molecular-weight (HMW) protein excretion rates were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis of urine samples. Kidney ultrastructure was examined through a transmission electron microscope (TEM).


RESULTS
IR resulted in significant LMW and HMW proteinuria. L-Nil significantly prevented the IR-induced increases in TP, albumin, and alpha1-microglobulin excretion. TEM showed loss of microvilli of the proximal tubule cells, injured mitochondria, and foamy changes in the structure of nuclear and cytoplasm in IR group. L-Nil reduced IR-mediated renal ultrastructural changes and tubular proteinuria.


CONCLUSIONS
This study suggested possible differences in the mechanism(s) of nephrotoxicity induced by iNOS in the glomeruli and tubular cells. The types of proteins excreted in the urine should be considered in the treatment strategy. In conclusion, this study suggested the involvement of iNOS in IR-induced tubular proteinuria.
Kadkhodaee
M
M
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. kadkhodm@tums.ac.ir
Zahmatkesh
M
M
Sadeghipour
H R
HR
Eslamifar
A
A
Taeb
J
J
Shams
A
A
Mahdavi-Mazdeh
M
M
D000818:Animals; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006339:Heart Rate; D008239:Lysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology; D015427:Reperfusion Injury / Q000503:physiopathology*
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D008239:Lysine