Angiotensin II stimulates expression of transforming growth factor β receptor type II in cultured mouse proximal tubular cells
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Tubulointerstitial fibrosis is a common end-point of many chronic renal diseases and contributes to the permanent loss of renal function. There is increasing evidence that the profibrogenic cytokine transforming growth factor TGF) β plays an essential role in this process by inducing the production of extracellular matrix proteins by tubular cells through an autocrine mechanism. We have previously demonstrated that the vasopeptide angiotensin (ANG) II induces TGF-β transcription and synthesis in cultured murine proximal tubular cells (MCT cell line). Since the overall effects of TGF-β on a distinct target cell may also depend on the expression of specific cell surface receptors, the present study was undertaken to test the hypothesis that ANG II modulates expression of TGF-β receptors in MCT cells. ANG II stimulated protein expression of TGF-β receptor type II, but not that of type I, in MCT cells as detected by immunofluorescence and western blotting of cell lysates. This stimulated receptor expression was also reflected in an overall increase in specific binding of 125I-labeled TGF-β1 to intact MCT cells. Coincubation with ANG II and an AT1 receptor antagonist abolished this increase in 125I-labeled TGF-β1 binding. Furthermore, ANG II also increased steady-state mRNA expression for TGF-β receptor type II. This stimulation was transduced through AT1 receptors and was independent of TGF-β released into the culture medium. Transient transfection studies using various length enhancer/promoter elements of the human TGF-β receptor type II linked to the CAT gene revealed that AP1 sites are a necessary prerequisite for ANG II induced transcriptional activity. ANG II had no effect on TGF-β receptor types I or II protein or on mRNA expression in syngeneic mesangial cells. Our results provide for the first time convincing evidence that ANG II upregulates TGF-β receptor type II expression on proximal tubular cells. Since this subtype of receptor is primarily engaged in the initial binding of TGF-β, an increased receptor expression may result in amplification of the TGF-β effects on tubular cells. Interference with an activated renin-angiotensin system could therefore counteract the profibrogenic effects of TGF-β by abolishing ANG II induced expression of TGF-β receptor type II.
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