TUBULAR GELATINASE-A (MMP-2) AND ITS TISSUE INHIBITORS IN POLYCYSTIC KIDNEY-DISEASE IN THE HAN-SPRD RAT

Thickening of the tubular basement membrane is one of the hallmarks of polycystic kidney disease (PKD). The present study was conducted to i nvestigate the potential role of the matrix metalloproteinase-2 (MMP-2 ) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumu lation of matrix components in PKD. As a model of PKD, two-month-old h eterozygous Han:SPRD rats, which are at an early stage of cystogenesis , were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysi n) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRN A level. In tubules from PKD rats MMP-2 activity was lower (31 +/- 8 v s. 58 +/- 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 /- 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 +/- 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 +/- 1.1- fold and TIMP-2 mRNA 3.8 +/- 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduc ed in PKD, due to downregulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that t hese alterations relate to the enhanced matrix accumulation observed i n the evolution of PKD.