Inhibition of the matrix metalloproteinase system in a rat model of chronic cyclosporine nephropathy

Abstract

Chronic cyclosporine A (CsA)-induced nephropathy is histologically characterized by tubular lesions, the interstitial recruitment of inflammatory cells, arteriolopathy and focal interstitial fibrosis. Recent studies show that the intrarenal inhibition of matrix degradation and recruitment of monocytes/ macrophages into the kidney plays a critical role in the development of renal interstitial fibrosis. We examined the expression of components of the matrix metalloproteinase (MMP) system and plasminogen activator inhibitor type-1 (PAI-1) in kidneys from rats injected daily s.c. during three weeks with CsA (10, 15 or 20 mg CsA/kg body wt) or vehicle solution. In all CsA-treated rats, serum creatinine levels were significantly elevated compared to control levels. The extent of CsA-induced atrophy was not influenced by the dosage during a three-week CsA treatment. The administration of CsA did not significantly increase total cortical interstitial collagen deposition, whereas alpha-smooth muscle actin expression was significantly increased in all CsA-treated rats. Analysis of the different subpopulations of inflammatory cells recruited into the chronically injured kidney revealed a marked influx of macrophages into fibrotic cortical foci of CsA-treated rats. The number of cortical macrophages was highest in the group receiving the highest CsA dose. PAI-1 antigen, present in proximal tubular lysosomes in kidneys from all experimental groups, stained very intensely in atrophic tubules in CsA-treated rats. Both stromelysin and interstitial collagenase mRNA were expressed in the kidneys of control rats, but their message transcription remained unaltered after CsA treatment. In contrast, the expression of tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) was significantly 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 sections of CsA-treated rats identified the cells responsible for the increased TIMP-1 message transcription after CsA administration, mainly as interstitial cells and also as visceral and parietal epithelial cells. These results suggest that the locally increased expression of TIMP-1 rather than a decrease of matrix metalloprotease expression, contributes to the development of CsA-induced focal interstitial fibrosis in the rat.