Submitted on July 16, 2007
Accepted on October 22, 2007
Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor kappa B activation
Sun-Young Hwang1, Connie W.H. Woo2, Kathy K.W. Au-Yeung1, Yaw L. Siow2, Tong Y. Zhu3, and Karmin O4*
1 Animal Science, University of Manitoba, Winnipeg, Canada
2 Physiology, University of Manitoba, Winnipeg, Canada
3 Integrative Biology Lab, St. Boniface Hospital Research Centre, Winnipeg, Canada
4 Animal Science, University of Manitoba, Winnipeg, Canada; Integrative Biology Lab, St. Boniface Hospital Research Centre, Winnipeg, Canada; Physiology, University of Manitoba, Winnipeg, Canada
* To whom correspondence should be addressed. E-mail: karmino{at}sbrc.ca.
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 homocysteine (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 kappa-B (NF-kB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underling 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 weeks. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-kB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-kB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-kB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-kB oligodeoxynucleotide to inhibit NF-kB 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-kB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia.
