INHIBITION OF THE MATRIX METALLOPROTEINASE SYSTEM IN A RAT MODEL OF CHRONIC CYCLOSPORINE NEPHROPATHY

Background. Chronic cyclosporine A (CsA)-induced nephropathy is histol ogically characterized by tubular lesions, the interstitial recruitmen t of inflammatory cells, arteriolopathy and focal interstitial fibrosi s. Recent studies show that the intrarenal inhibition of matrix degrad ation and recruitment of monocytes/ macrophages into the kidney plays a critical role in the development of renal interstitial fibrosis. Met hods. We examined the expression of components of the matrix metallopr oteinase (MMP) system and plasminogen activator inhibitor type-1 (PAI- 1) in kidneys from rats injected daily s.c. during three weeks with Cs A (10, 15 or 20 mg CsA/kg body wt) or vehicle solution. Results. In al l CsA-treated rats, serum creatinine levels were significantly elevate d compared to control levels. The extent of CsA-induced atrophy was no t influenced by the dosage during a three-week CsA treatment. The admi nistration of CsA did not significantly increase total cortical inters titial collagen deposition, whereas cu-smooth muscle actin expression was significantly increased in all CsA-treated rats. Analysis of the d ifferent subpopulations of inflammatory cells recruited into the chron ically injured kidney revealed a marked influx of macrophages into fib rotic cortical foci of CsA-treated rats. The number of cortical macrop hages was highest in the group receiving the highest CsA dose. PAI-1 a ntigen, present in proximal tubular lysosomes in kidneys from all expe rimental groups, stained very intensely in atrophic tubules in CsA-tre ated rats. Both stromelysin and interstitial collagenase mRNA were exp ressed in the kidneys of control rats? but their message transcription remained unaltered after CsA treatment. In contrast, the expression o f tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) was sig nificantly increased after CsA treatment. TIMP-1 mRNA was undetectable in renal sections from sodium-depleted vehicle-treated animals using the in situ hybridization (ISH) technique. ISH of selected renal secti ons of CsA-treated rats identified the cells responsible for the incre ased TIMP-1 message transcription after CsA administration, mainly as interstitial cells and also as visceral and parietal epithelial cells. Conclusions. These results suggest that the locally increased express ion of TIMP-1 rather than a decrease of matrix metalloprotease express ion, contributes to the development of CsA-induced focal interstitial fibrosis in the rat.