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

Background. Chronic nephrotoxicity is an important adverse effect of cyclos porine 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 d epends 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), W e previously showed that sclerosis-prone and sclerosis-resistant phenotypes are maintained in vitro, We examined whether CsA exposure directly affecte d extracellular matrix turnover in mesangial cells and whether the response is determined by the genetic background, Extracellular matrix synthesis an d degradation were studied by proline incorporation, ELISA, reverse transcr iption-polymerase chain reaction, zymography, and reverse zymography, We ch ose a CsA dose that induced neither cytotoxicity nor apoptosis (1 mu g/ml), Results. At the dose of 1 mu g/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-beta(1) mRN A expression and protein synthesis in either cell line. Conclusion. CsA increases total collagen accumulation in mesangial cells fr om sclerosis-prone mice by decreasing MMP-2 activity, but does not affect c ells from sclerosis-resistant mice. Thus, CsA directly affects mesangial ce lls, but only those with a permissive genetic background for glomeruloscler osis.