ALTERED EXPRESSION OF MATRIX METALLOPROTEINASE-2 TIMP, AND TIMP-2 IN OBSTRUCTIVE NEPHROPATHY

We have previously characterized the evolution of renal cortical inter stitial fibrosis in the rabbit model of unilateral ureteral obstructio n (UUO). In our earlier report, we examined the extracellular matrix p rotein composition of the interstitial space. Of note, UUO was associa ted with the acquisition of prominent interstitial collagen IV immunor eactivity. Interstitial collagens I and III were also increased. In si tu hybridization localized increased expression of collagens I and iv to cells of the interstitial space, In the current study, we examine m etalloproteinase and metalloproteinase inhibitor expression in the obs tructed renal cortex Matrix metalloproteinase-2 is a metalloproteinase with activity against both collagen Iv and denatured collagen I. At d ay 3 of UUO, both transcripts were significantly increased, although e xpression of these mRNAs was not different from controls after 7 and 1 6 days of UUO. Expression of mRNA of tissue inhibitor of the metallopr oteinases (TIMP) was significantly increased in the UUO samples at all times, although it was maximal at day 3. Immunohistochemically, incre ased TIMP reactivity localized to the interstitial space, and TIMP mRN A expression was seen to parallel the interstitial macrophage infiltra tion that accompanies ureteteral obstruction. In contrast, TIMP-2 mRNA expression appeared to be biphasic, with peaks at both day 3 and day 16 of UUO. At day 7, expression was not different from controls. These data suggest a role for impaired matrix degradation in the developmen t of interstitial fibrosis in the obstructed kidney, particularly at l ate times when collagen mRNA expression has returned to control values .