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Division of Nephrology and Hypertension, Harbor-UCLA Medical Center and University of California Los Angeles, Torrance, California 90509
Glomerular
proteinuria is a risk factor for progression of chronic renal failure
and contributes to renal interstitial fibrosis. In experimental
diabetic glomerular sclerosis, there is translocation of
high-molecular-weight growth factors, namely, hepatocyte growth factor
(HGF) and transforming growth factor (TGF)-
, from plasma into
tubular fluid, both of which act on tubular cells through apical
membrane receptors. In the present studies, the hypothesis is examined
that ultrafiltered HGF and TGF- induce increased expression of
extracellular matrix (ECM) proteins directly in tubular cells, or
induce increased expression of cytokines that may act on interstitial
myofibroblasts. Incubation of cultured tubular cells with recombinant
human (rh) TGF- modestly raises expression of collagen type III, but
rhHGF dose dependently blocks expression of this ECM protein. Both
growth factors raise fibronectin expression up to fourfold and increase
expression of platelet-derived growth factor (PDGF)-BB up to sixfold,
but not of fibroblast growth factor-2. Pooled, diluted glomerular
ultrafiltrate that had been collected by nephron micropuncture from
rats with diabetic nephropathy (24-30 wk) also raises expression
of fibronectin as well as PDGF-BB in proximal tubular cells. In the
presence of neutralizing antibodies that block actions of HGF and
TGF-, diabetic rat glomerular ultrafiltrate fails to increase
tubular cell PDGF-BB expression. In NRK-49F renal interstitial
myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen
type III but not type I or fibronectin. The findings provide evidence
for ultrafiltered HGF and TGF- to contribute to interstitial
accumulation of ECM proteins by direct effects on tubular cells as well
as indirect mechanisms, via PDGF-BB and its action on myofibroblasts.
These events may be important mechanisms of proteinuria-induced renal
interstitial fibrosis and accelerated progression of chronic renal
failure in diabetic nephropathy and perhaps other proteinuric
glomerular diseases.
collagen; fibronectin; renal interstitial fibrosis
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