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 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.
Sheffield Kidney Institute, Northern General Hospital N.H.S. Trust, England, United Kingdom.
M
M
Shehata
G H
GH
Cope
T S
TS
Johnson
A T
AT
Raftery
A M
AM
el Nahas
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016212:Transforming Growth Factor beta; D016572:Cyclosporine