Association between hyperhomocysteinemia and vascular dysfunction on molecular basis in acute and chronic models of experimental renal failure-possible role of folic acid

ABSTRACT

Hyperhomocysteinemia [HHcy] has recently been suggested as a risk factor for atherosclerosis [AS] in patients with chronic renal disease. Several mechanisms for HHcy-induced AS have been proposed but the molecular pathogenesis of this relation is still unclear. So far, there are no reports showing the changes in homocysteine levels in acute renal failure. We investigated whether HHcy is a common finding in acute and chronic renal failure, its relation to the pathogenesis of vascular dysfunction and its possible treatment by folic acid. 35 rats were divided into 5 groups [Gp] Gp1 [sham operated]; Gp2 [acute ischemic renal failure]; Gp3 [treated acute ischemic renal failure]; Gp4 [chronic renal failure]; Gp5 [treated chronic renal failure]. Blood samples were collected for determination of urea, creatinine and homocysteine. Aortae were harvested for assessment of vascular endothelial growth factor [VEGF] expression and aortic content of tumor necrosis factor alpha [TNF]. Both acute [Gp2] and chronic [Gp4] models of renal failure showed higher homocysteine concentrations; increased VEGF expression and increased TNF alpha than Gpl. Folic acid treatment caused significantly lower homocysteine levels and VEGF expression in Gp3 and Gp5 than Gp2 and Gp4, while its reducing effect on TNF was only evident in acute treated model compared to Gp2. Homocysteine significantly correlates with creatinine and VEGF expression in acute models [Gp2 and 3], with urea, creatinine, TNF alpha in chronic model [Gp4] and with TNF alpha in Gp5. Our findings demonstrate that HHcy is evident in acute and chronic renal failure. Increased VEGF expression in acute failure and enhanced vascular inflammation in chronic failure could be possible mechanisms by which HHcy accelerates AS. However, the direct causal relationship between them needs further investigations. Folic acid decreases HHcy and could be useful in reducing cardiovascular risk factors in uremic patients