Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Abstract

Thickening of the tubular basement membrane is one of the hallmarks of polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP3 (stromelysin) 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 mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 ± 8 vs. 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 TIMP-2 activity is reduced 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 these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.