G. Wolf et al., Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells, J MOL MED-J, 77(7), 1999, pp. 556-564
Citations number
33
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Tubulointerstitial fibrosis is a common endpoint of many chronic renal dise
ases and contributes to the permanent loss of renal function. There is incr
easing evidence that the profibrogenic cytokine transforming growth factor
TGF) beta plays an essential role in this process by inducing the productio
n of extracellular matrix proteins by tubular cells through an autocrine me
chanism. We have previously demonstrated that the vaso-peptide angiotensin
(ANG) II induces TGF-beta transcription and synthesis in cultured murine pr
oximal 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 ce
ll surface receptors, the present study was undertaken to test the hypothes
is 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 tha
t of type I, in MCT cells as detected by immunofluorescence and western blo
tting of cell lysates. This stimulated receptor expression was also reflect
ed 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 antagon
ist abolished this increase in I-125-labeled TGF-beta(1) binding. Furthermo
re, ANG II also increased steady-state mRNA expression for TGF-beta recepto
r type II. This stimulation was transduced through AT(1) receptors and was
independent of TGF-beta released into the culture medium. Transient transfe
ction studies using various length enhancer/promoter elements of the human
TGF-beta receptor type Il linked to the CAT gene. revealed that AP1 sites a
re a necessary prerequisite for ANG II induced transcriptional activity. AN
G II had no effect: on TGF-beta receptor types I or II protein or on mRNA e
xpression in syngeneic mesangial cells. Our results provide for the first t
ime convincing evidence that ANC II upregulates TGF-beta receptor type II e
xpression on proximal tubular cells. Since this subtype of receptor is prim
arily engaged in the initial binding of TGF-beta, an increased receptor exp
ression may result in amplification of the TGF-beta effects on tubular cell
s. Interference with an activated renin-angiotensin system could therefore
counteract the profibrogenic effects of TGF-beta by abolishing ANG II induc
ed expression of TGF-beta receptor type II.