Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis

Abstract

The pathophysiologic sequelae of both acute and chronic experimental unilateral ureteral obstruction (UUO) in the rat are the result of a variety 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 laboratory, among others, has shown an up-regulated expression of renal cortical transforming growth factor (TGF)-β1 within hours of the onset of UUO. Because a potential contribution of TGF-β to fibrosis may be its ability to increase the expression of proteinase inhibitors such as members of the tissue inhibitor of metalloproteinase (TIMP) family, this laboratory now sought to delineate the kinetics of TIMP-1, TIMP-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 compared with the contralateral unobstructed kidney or sham-operated rat specimens. In contradistinction to TIMP-1, a decrease in TIMP-3 mRNA levels 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 that the increased expression of TGF-β1 post-UUO induces a profibrogenic state and initiates a cascade of dysregulatory events including the up-regulation of TIMP-1. TIMP-2 mRNA expression appears to be independently regulated from TIMP-1, and TGF-β1 fails to modulate its mRNA level during the early phases of ureteral obstruction. Of interest, a significant down-regulation of renal cortical TIMP-3 mRNA levels was observed in the obstructed kidneys; however, the pathophysiologic significance of this finding remains to be elucidated.