CyA-Mediated Renal Interstitial and Vascular Lesions in the Rat under Low-Sodium Diet

Nephrotoxicity of CyA was analyzed histologically in rats fed a low-sodium diet. CyA was subcutaneously administered daily at a dose of 15 mg/kg for 10 or 35 days with or without prior uninephrectomy (UNT) in male Sprague-Dawley rats receiving a low-sodium diet (0.03% sodium). CyA-administered rats showed impaired renal function as well as tubulo-interstitial lesions, such as edema, tubular basement membrane changes, and tubular atrophy, in the cortex, especially in the subcapsular portion, within 10 days. On day 35, the tubulo-interstitial lesions were advanced with mild focal interstitial fibrosis. These lesions were mild in the UNT group compared to the non-UNT group. Immunohistochemically, CyA treatment caused an increase in number of renin-positive cells in the afferent arteriolar wall at juxtaglomerular area. These cells lost the expression of calponin, which is a marker of mature smooth muscle cells. In addition, in afferent arterioles and interlobular arteries, electron-dense fibrous bodies were found in the smooth muscle cells on days 10 and 35. Immunoelectron microscopically, these bodies showed scattered positive staining for calponin and α-actinin, were negative or only peripherally positive for α-SMA and vimentin, and were completely negative for desmin. This study revealed that CyA could cause interstitial lesions starting in the subcapsular portion of the renal cortex and vascular lesions of the preglomerular artery. Increases in number of renin granules and formation of cytoplasmic fibrous bodies in smooth muscle cells could be the forerunner of severe arteriolar wall damage.