Nephrology Dialysis Transplantation, Vol 13, Issue 11 2804-2813, Copyright © 1998 by Oxford University Press
R Weiss and A Ramirez
Background: Glomerulonephritis is characterized by the
accumulation of extracellular matrix protein within the glomerulus. This
process, when allowed to proceed unimpeded, leads to glomerulosclerosis and
eventually to cessation of glomerular filtration. There is evidence that
protein kinase C (PKC) activation plays an important role in mediating at
least some of the effects of TGF-{beta} in vascular smooth-muscle cells.
The current study was undertaken to determine whether PKC activity is
required for both TGF-{beta} and angiotensin II (Ang II) to induce
mesangial cell matrix protein secretion. Methods: PKC
was inhibited by two separate methods, and
[3H]thymidine incorporation was assessed in both the
presence and the absence of PKC inhibition. Conditioned medium from cells
stimulated with TGF-{beta} or Ang II was collected and analysed for
secreted matrix proteins and sulphated proteins by SDS-polyacrylamide gel
electrophoresis and western blotting. Results:
Twenty-four-hour incubation of rat mesangial cells with
phorbol-12-myristate-13-acetate (PMA) reduced total PKC activity to basal
levels. Both TGF-{beta} and Ang II were mitogenic in mesangial cells,
and chronic PMA pre-incubation inhibited this DNA synthesis. TGF-{beta}
and Ang II-induced sulphated protein secretion into conditioned medium was
markedly attenuated in PKC-downregulated cells. Secretion of the specific
matrix proteins laminin and fibronectin by mesangial cells stimulated with
either TGF-{beta} or Ang II was also diminished in PKC-downregulated
cells and in cells pre-incubated with the specific PKC inhibitor,
chelerythrine. There was no evidence of generalized cell toxicity or
decreased non-specific protein synthesis caused by these PKC inhibitors.
Conclusions: PKC is a key intermediary in the process
by which TGF-{beta} and Ang II cause DNA synthesis and mesangial cell
matrix protein production. Thus, PKC inhibitors deserve further study as
potential therapeutic agents for a variety of glomerular diseases.
Key words: angiotensin; mesangial cell; phorbol;
protein kinase C; proteoglycan; TGF-{beta}
ORIGINAL ARTICLES
TGF-{beta}- and angiotensin-II-induced mesangial matrix protein secretion is mediated by protein kinase C
Department of Veterans' Affairs, Northern California System of Clinics, Pleasant Hill, CA, USA; Corresponding author at: Division of Nephrology, TB 136, Department of Internal Medicine, University of California, Davis, CA 95616, USA
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