Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-kappaB activation.
Hyperhomocysteinemia, or an elevation of blood homocysteine (Hcy) levels, is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of Hcy on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor-kappaB (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underlining such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 wk. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-kappaB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-kappaB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-kappaB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-kappaB oligodeoxynucleotide to inhibit NF-kappaB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-kappaB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia.
Hwang
Sun-Young
SY
Department of Animal Science, University of Manitoba, Winnipeg, Canada.
Woo
Connie W H
CW
Au-Yeung
Kathy K W
KK
Siow
Yaw L
YL
Zhu
Tong Y
TY
O
Karmin
K
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger; D006710:Homocysteine; D008715:Methionine