DIFFERENTIAL MESSENGER-RNA EXPRESSION OF RENAL CORTICAL TISSUE INHIBITOR OF METALLOPROTEINASE-1, METALLOPROTEINASE-2, AND METALLOPROTEINASE-3 IN EXPERIMENTAL HYDRONEPHROSIS

The pathophysiologic sequelae of both acute and chronic experimental u nilateral ureteral obstruction (UUO) in the rat are the result of a va riety of complex humoral and cellular interactions, The development of interstitial fibrosis is dependent on the tightly coupled regulation of synthesis and degradation of extracellular matrix proteins. This la boratory, among others, has shown an up-regulated expression of renal cortical transforming growth factor (TGF)-beta 1 within hours of the o nset of UUO, Because a potential contribution of TGF-P to fibrosis may be its ability to increase the expression of proteinase inhibitors su ch as members of the tissue inhibitor of metalloproteinase (TIMP) fami ly, this laboratory now sought to delineate the kinetics of TIMP-1, TI MP-2, and TIMP-3 mRNA expression in the renal cortex after UUO, There was a marked elevation of TIMP-1 mRNA expression after UUO, which was first noted at 12 h after ureteral ligation. By 96 h after UUO, there was a 30-fold increment in TIMP-1 mRNA in the obstructed kidneys compa red with the contralateral unobstructed kidney or sham-operated rat sp ecimens, In contradistinction to TIMP-1, a decrease in TIMP-3 mRNA lev els was noted at 12 h after ureteral obstruction and persisted at the 24-, 48-, and 96-h time intervals. TIMP-2 gene expression remained at a relatively constant level during the entire study. It is proposed th at the increased expression of TGF-beta 1 post-UUO induces a profibrog enic state and initiates a cascade of dysregulatory events including t he up-regulation of TIMP-1. TIMP-2 mRNA expression appears to be indep endently regulated from TIMP-1, and TGF-beta 1 fails to modulate its m RNA level during the early phases of ureteral obstruction. Of interest , a significant down-regulation of renal cortical TIMP-3 mRNA levels w as observed in the obstructed kidneys; however, the pathophysiologic s ignificance of this finding remains to be elucidated.