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Kidney Int. 2002 Oct;62(4):1219-28.

Renal tubulointerstitial injury in weanling rats with hyperhomocysteinemia.

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Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.



While hyperhomocysteinemia is associated with an increased risk of atherosclerosis and the related cardiovascular diseases, the effect of hyperhomocysteinemia on the kidney has not been clearly demonstrated. The purpose of this study was to investigate whether long-term hyperhomocysteinemia develops atherosclerotic lesions in the kidney.


The effects of various dietary combinations, including folate deficiency, choline deficiency and methionine loading, on the plasma homocysteine concentration, renal function and renal histopathology were examined for 12 weeks in male weanling Fisher rats.


Folate deficiency, choline deficiency and methionine loading synergistically induced hyperhomocysteinemia up to 69.7 +/- 23.1 micromol/L (control, 11.6 +/- 3.9 micromol/L, P < 0.01) without any change in blood pressure. Creatinine clearance was negatively correlated with the plasma homocysteine concentration (r = -0.55, P < 0.01). Arterial and arteriolar wall thickening, and focal tubulointerstitial fibrosis were found in the kidneys of the hyperhomocysteinemic rat. The lesions of tubulointerstitial fibrosis appeared striped or wedge-shaped at the subcapsular cortex of the kidney. In addition, the expression of vascular endothelial growth factor, an indicator of hypoxia, was increased in the adjacent more intact area of the cortex. These findings suggest that the renal tubulointerstitial lesions were likely to be mediated by severe ischemia due to regional circulatory disturbance. Folate supplementation diminished these vascular and tubulointerstitial changes.


These results indicate that diet-induced chronic hyperhomocysteinemia could induce vascular remodeling and tubulointerstitial injury in the kidney, and that these changes were ameliorated by folate supplementation.

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