Cyclosporine enhances the expression of TGF-β in the juxtaglomerular cells of the rat kidney

Abstract

The mediators of cyclosporine (CsA) nephrotoxicity remain ill defined. In this study, we describe evidence of increased amounts of transforming 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 electron microscope levels and Northern blot analysis was applied to detect changes in transcription of TGF-beta. In control rats, weak to moderate 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 intensity of staining. The number of stained afferent arterioles increased from a control value of 0.21 +/- 0.08/mm2 cortex to 0.84 +/- 0.15/mm2 cortex, P < 0.01, and to 1.12 +/- 0.10/mm2 cortex, P < 0.01, in 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/mm2 to 0.31 +/- 0.02/mm2, P < 0.05, and 0.39 +/- 0.07/mm2, P < 0.01, in rats treated with CsA, 12.5 mg/kg/day and 25 mg/kg/day, respectively. At the electron microscope level, TGF-beta was localized exclusively within the granular cells of the juxtaglomerular arterioles. Northern blot analysis suggested that this enhanced staining is due to increased transcription of TGF-beta 1. We have therefore observed an association between TGF-beta and CsA-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 induced nephrotoxicity.

FK506 inhibits the mice glomerular mesangial cells proliferation by affecting the transforming growth factor-βand Smads signal pathways

“…[4][5][6][7] TGF-b1 can induce the expression and synthesis of fibronectin in human mesangial cells. [8][9][10] The discovery of Smads further reveals the mechanism of action of TGF-b.…”

In Vitro and In Vivo Transfection of p21 Gene Enhances Cyclosporin A-Mediated Inhibition of Lymphocyte Proliferation

“…We and others have demonstrated that both cyclosporine and tacrolimus induce TGF-␤, which has both potent antiproliferative as well as fibrogenic effects (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The significance of these latter effects on the immunosuppressive properties of these agents is still under active investigation; however, our own studies have suggested that TGF-␤ appears to mimic much of the in vivo effects of cyclosporine in a mouse model (2).…”

“…Cyclosporine and tacrolimus, in addition to their effect on inhibiting IL-2, induce the expression of TGF-␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). This effect may be partially responsible for the antiproliferative effects of cyclosporine as well as responsible for the majority of the fibrogenic-related toxic effects of this agent, most importantly the nephrotoxicity.…”

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

“…Therefore, tubulo-interstitial lesions caused by CyA treatment could not be explained by hypoxia only, at least in rats. There have been some reports of similar subcap- sular lesions in rats caused by CyA treatment (33,36), but the precise mechanism has not been determined.…”

“…These (16,19) but did not induce hypertension (35,41). Systemic hypertension has been reported to be caused by CyA treatment in rats (5,18,27,29,33). The rise of blood pressure may be influenced by differences in strains, dose of CyA, or type of vehicle used.…”