Vascular Endothelin, TGF-beta and PDGF Expression in FK506 Nephrotoxicity of Rats

Jeong, Hyeon Joo; Kim, Yu Seun; Hong, In Chul

Abstract

The vascular lesions in FK506 nephrotoxicity are similar to cyclosporine A, in which mediators related to vascular constriction and thickening such as endothelin, TGF-beta and PDGF may have some roles. Their expressions may be different in terms of degree and time sequence as well as overlapping ischemia, which made us to perform this experiment. Male Sprague Dawley rats received FK506 daily at a dosage of 2 mg/kg by intramuscular route for 4 weeks at maximum and were sacrificed 3 days, 1, 2 and 4 weeks after the initiation of the study, respectively. The control rats received saline. Renal ischemia was induced by occluding the left renal artery for 45 minutes and rats were sacrificed up to 2 weeks after reperfusion. Kidneys were processed for light microscopy and stained with PAS method and with antibodies against endothelin, TGF-beta and PDGF. The number of juxtaglomerular apparatus(JGA) and arterioles positive for each antibody was counted under light microscope and was expressed as mean +/- S.D per mm2 cortex. In FK506 treated rats, JGA and afferent arterioles were prominent with PAS positive granules, which was extended proximally to interlobular arteries with increased duration of FK506 treatment. With increasing duration, TGF-beta reactivity was increased in afferent arterioles. However, no such results were shown in cases of PDGF and endothelin. Renal ischemia itself increased vascular TGF-beta as well as endothelin and PDGF reactivities. Renal ischemia in FK506 treated rats further upregulated the expression of these markers in a similar distribution. However, the expression of endothelin was mostly found in endothelial cells of peritubular and glomerular capillaries. PAS staining was decreased in ischemic kidneys regardless of FK506 treatment. These results indicate that FK506 toxicity was comparable to CsA toxicity. Since expression levels of endothelin, TGF-beta and PDGF were increased in ischemic kidney, it might be helpful to prevent ischemic damage as well as to hinder secretion of these factors in order to reduce FK506 nephrotoxicity.