Hyperhomocysteinemia induces renal hemodynamic dysfunction: is nitric oxide involved?
Hyperhomocysteinemia is associated with endothelial dysfunction, although the underlying mechanism is unknown. Previous studies have shown that nitric oxide (NO) plays an important role in the regulation of systemic and renal hemodynamics. This study investigated whether hyperhomocysteinemia induces renal oxidative stress and promotes renal dysfunction involving disturbances of the NO-pathway in Wistar rats. During 8 wk, control (C) and hyperhomocysteinemic (HYC) groups had free access to tap water and homocysteine-thiolactone (HTL, 50 mg/kg per d), respectively. At 8 wk, plasma homocysteine concentration, renal superoxide anion (O(2)), nitrotyrosine, and nitrite+nitrate levels, and renal function were measured. To assess NO involvement, the responses to L-Arginine (L-Arg, 300 mg/kg) and N(G)-nitro-L-arginine-methyl-ester (L-NAME, 20 microg/kg per min for 60 min) were analyzed. The HYC group showed higher homocysteine concentration (7.6 +/- 1.7 versus 4.9 +/- 1.0 micromol/L; P < 0.001), (O(2) production (157.92 +/- 74.46 versus 91.17 +/- 29.03 cpm. 10(3)/mg protein), and nitrite+nitrate levels (33.4 +/- 5.1 versus 11.7 +/- 4.3 micro mol/mg protein; P < 0.001) than the control group. Western blot analyses showed a nitrotyrosine mass 46% higher in the HYC group than in the controls. Furthermore, the HYC group showed lower GFR, renal plasma flow (RPF), and higher renal vascular resistance (RVR) than the controls. After L-Arg administration, the responses of GFR, RPF, and RVR were attenuated by 36%, 40%, and 50%, respectively; after L-NAME, the responses of RPF and RVR were exaggerated by 79% and 112%, respectively. This suggests a reduced NO bioavailability to produce vasodilation and an enhanced sensitivity to NO inhibition. In conclusion, hyperhomocysteinemia induces oxidative stress, NO inactivation, and renal dysfunction involving disturbances on the NO-pathway.
Fischer
Patricia A
PA
Section of Pharmacology, Department of Physiology, Favaloro University, Buenos Aires, Argentina.
Dominguez
Graciela N
GN
Cuniberti
Luis A
LA
Martinez
Verónica
V
Werba
José P
JP
Ramirez
Agustín J
AJ
Masnatta
Lucas D
LD
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000378:metabolism* / Q000503:physiopathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D017392:Thiobarbituric Acid Reactive Substances; D006710:Homocysteine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D006152:Cyclic GMP