Angiotensin II stimulates expression of transforming growth factor β receptor type II in cultured mouse proximal tubular cells

Tubulointerstitial fibrosis is a common endpoint 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) beta 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 vaso-peptide angiotensin (ANG) II induces TGF-beta transcription and synthesis in cultured murine proximal tubular cells (MCT cell line). Since the overall effects of TGF-beta 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 ANC ii modulates expression of TGF-beta receptors in MCT cells. ANC IT stimulated protein expression of TCF-beta receptor type IT, 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 I-125-labeled TGF-beta(1) to intact MCT cells. Coincubation with ANC II and an AT(1) receptor antagonist abolished this increase in I-125-labeled TGF-beta(1) binding. Furthermore, ANG II also increased steady-state mRNA expression for TGF-beta receptor type II. This stimulation was transduced through AT(1) receptors and was independent of TGF-beta released into the culture medium. Transient transfection studies using various length enhancer/promoter elements of the human TGF-beta receptor type Il 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-beta receptor types I or II protein or on mRNA expression in syngeneic mesangial cells. Our results provide for the first time convincing evidence that ANC II upregulates TGF-beta receptor type II expression on proximal tubular cells. Since this subtype of receptor is primarily engaged in the initial binding of TGF-beta, an increased receptor expression may result in amplification of the TGF-beta effects on tubular cells. Interference with an activated renin-angiotensin system could therefore counteract the profibrogenic effects of TGF-beta by abolishing ANG II induced expression of TGF-beta receptor type II.