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

Fornoni, Alessia1; Lenz, Oliver1; Tack, Ivan1; Potier, Mylene1; Elliot, Sharon J.1; Striker, Liliane J.1 2; Striker, Gary E.1

Experimental Transplantation

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-+Es1b/+Es1a, 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 μg/ml).

Results. At the dose of 1 μg/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-β1 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.

Renal Cell Biology Laboratory, Division of Nephrology, University of Miami School of Medicine, Miami, Florida

1 Renal Cell Biology Laboratory.

Received 13 October 1999.

Accepted 16 March 2000.

2 Address correspondence to: Liliane J. Striker, M.D., University of Miami School of Medicine, Post Office Box 016960 (R126), Miami, Florida 33101. E-mail: lstriker@med.miami.edu.

© 2000 Lippincott Williams & Wilkins, Inc.