MATRIX ACCUMULATION IN MESANGIAL CELLS EXPOSED TO CYCLOSPORINE A REQUIRES A PERMISSIVE GENETIC BACKGROUND

Alessia Fornoni, Oliver Lenz, Ivan Tack, Mylene Potier, Sharon J. Elliot, Liliane J. Striker, Gary E. Striker
Transplantation. 2000-08-01; 70(4): 587-593
DOI: 10.1097/00007890-200008270-00009

PubMed

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1. Transplantation. 2000 Aug 27;70(4):587-93. doi:
10.1097/00007890-200008270-00009.

Matrix accumulation in mesangial cells exposed to cyclosporine A requires a
permissive genetic background.

Fornoni A(1), Lenz O, Tack I, Potier M, Elliot SJ, Striker LJ, Striker GE.

Author information:
(1)Division of Nephrology, University of Miami School of Medicine, Florida
33101, USA.

BACKGROUND: Chronic nephrotoxicity is an important adverse effect of
cyclosporine A (CsA) therapy. Tubulo-interstitial lesions and arteriolopathy are
common histologic findings. Glomerular lesions are also described, but they are
of variable severity. The aim of our study is to determine whether CsA has a
direct effect on mesangial cells and whether the cellular response depends on
the genetic background.
METHODS: We studied mesangial cells isolated from mice susceptible
(ROP/Le-+Es1(b)+Es1(a), ROP) and resistant to glomerulosclerosis (B6SJLF1, C57).
We previously showed that sclerosis-prone and sclerosis-resistant phenotypes are
maintained in vitro. We examined whether CsA exposure directly affected
extracellular matrix turnover in mesangial cells and whether the response is
determined by the genetic background. Extracellular matrix synthesis and
degradation were studied by proline incorporation, ELISA, reverse
transcription-polymerase chain reaction, zymography, and reverse zymography. We
chose a CsA dose that induced neither cytotoxicity nor apoptosis (1 microg/ml).
RESULTS: At the dose of 1 microg/ml total collagen accumulation was increased in
ROP but not in C57 cells. Matrix metalloproteinase (MMP)-2 activity and mRNA
levels were selectively decreased in ROP cells. CsA exposure did not affect
tissue inhibitors of MMP (TIMP)-1 and -2 activity or TGF-beta1 mRNA expression
and protein synthesis in either cell line.
CONCLUSION: CsA increases total collagen accumulation in mesangial cells from
sclerosis-prone mice by decreasing MMP-2 activity, but does not affect cells
from sclerosis-resistant mice. Thus, CsA directly affects mesangial cells, but
only those with a permissive genetic background for glomerulosclerosis.