Contribution of guanine nucleotide exchange factor Vav2 to hyperhomocysteinemic glomerulosclerosis in rats.
We currently reported that Vav2, a member of the guanine nucleotide exchange factor-Vav subfamily, participates in homocysteine-induced increases in Rac1 activity and consequent activation of NADPH oxidase in rat mesangial cells. However, the physiological relevance of this cellular action of Vav2 remains unknown. The present study tested a hypothesis that Vav2 importantly mediates the injurious action of homocysteine on glomeruli and thereby contributes to the development of glomerulosclerosis during hyperhomocysteinemia. We found that, among Vav members, Vav2 was abundantly expressed in glomeruli. When Vav2 short hairpin RNA was transfected into the kidneys of Sprague-Dawley rats, hyperhomocysteinemia induced by folate-free diet failed to significantly enhance Rac1 activity and increase NADPH-dependent superoxide production. In these rats with silenced renal Vav2 gene, glomerular injury during hyperhomocysteinemia was markedly attenuated compared with those rats only receiving mock vector transfection, as shown by ameliorated albuminuria and extracellular matrix metabolism. In the rat kidneys with transfection of a dominant-active Vav2 variant (onco-Vav2), we found that overexpression of Vav2 led to significant increases in Rac1 activity, superoxide production, and glomerular injury, which was similar to that induced by hyperhomocysteinemia. However, this Vav2 overexpression was unable to further enhance homocysteine-induced glomerular injury. We concluded that Vav2-mediated activation of NADPH oxidase is an important initiating mechanism resulting in hyperhomocysteinemic glomerular injury through enhanced local oxidative stress.
Yi
Fan
F
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, 410 N 12th St, Richmond, VA 23298, USA.
Xia
Min
M
Li
Ningjun
N
Zhang
Chun
C
Tang
Lin
L
Li
Pin-Lan
PL
D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D051567:Proto-Oncogene Proteins c-vav; D019715:Tissue Inhibitor of Metalloproteinase-1; C490564:Vav2 protein, rat; D006710:Homocysteine; D013481:Superoxides; D012313:RNA; D005492:Folic Acid; D019255:NADPH Oxidases; D020782:Matrix Metalloproteinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein