CYCLOSPORINE ENHANCES THE EXPRESSION OF TGF-BETA IN THE JUXTAGLOMERULAR CELLS OF THE RAT-KIDNEY

The mediators of cyclosporine (CsA) nephrotoxicity remain ill defined. In this study, we describe evidence of increased amounts of transform ing growth factor-beta (TGF-beta) in the kidneys of adult male Wistar rats treated with CsA (5 to 25 mg/kg/day) for four weeks. Localization of TGF-beta was undertaken immunocytochemically at both light and ele ctron microscope levels and Northern blot analysis was applied to dete ct changes in transcription of TGF-beta. In control rats, weak to mode rate immunostaining for TGF-beta was observed, in the juxtaglomerular arterioles. CsA treatment resulted in a dose-dependent increase in the number of stained afferent and interlobular arterioles and in the int ensity of staining. The number of stained afferent arterioles increase d from a control value of 0.21 +/- 0.08/mm(2) cortex to 0.84 +/- 0.15/ mm(2) cortex, P < 0.01, and to 1.12 +/- 0.10/mm(2) cortex, P < 0.01, i n rats treated with CsA 12.5 mg/kg/day and 25 mg/kg/day, respectively. The number of interlobular arterioles stained for TGF-beta increased from a control value of 0.07 +/- 0.05/mm(2) to 0.31 +/- 0.02/mm(2), P < 0.05, and 0.39 +/- 0.07/mm(2), P < 0.01, in rats treated with CsA, 1 2.5 mg/kg/day and 25 mg/kg/day, respectively. At the electron microsco pe level, TGF-beta was localized exclusively within the granular cells of the juxtaglomerular arterioles. Northern blot analysis suggested t hat this enhanced staining is due to increased transcription of TGF-be ta 1. We have therefore observed an association between TGF-beta and C sA-induced nephrotoxicity. While this does not establish a causal link , it leads us to postulate that TGF-beta, alone or in combination with other growth factors, may play a role in the pathogenesis of CsA indu ced nephrotoxicity.