ENALAPRIL ATTENUATES INCREASED GENE-EXPRESSION OF EXTRACELLULAR-MATRIX COMPONENTS IN DIABETIC RATS

This study was designed to assess whether the glomerular expression of mRNA for extracellular matrix (ECM) components including alpha 1 (I), alpha 1 (III), and (alpha 1 (IV) collagen chains, laminin B1 and B2 chains, metalloproteinases (MMP), and tissue inhibitor of metalloproteinases (TIMP) is affected by enalapril in 12- and 24-wk-old rat after streptozotocin injection. Animals were divided into three groups; untreated diabetic rats, enalapril-treated diabetic rats, and control rats. Enalapril treatment was continued for 24 wk. Enalapril reduced both creatinine clearance (P < 0.01) and urinary protein excretion (P < 0.01) in diabetic rats. In diabetic rats, mRNA levels for alpha 1(IV) collagen chain, laminin B1 and B2 chains, and (alpha 1(I) and alpha 1(III) collagen chains increased significantly at 24 wk compared with those in controls (alpha 1(IV): 3.8-fold (P < 0.01); laminin B1: 6.2-fold (P < 0.01); laminin B2: 5.4-fold (P < 0.01), alpha 1(I): 4.8-fold (P < 0.01) and (alpha 1(III): 3.8-fold (P < 0.01)). At 24 wk, mRNA levels for MMP-1 and MMP-3 fell to 40% (P < 0.01) and 20% (P < 0.01), respectively, in the glomeruli of diabetic rats compared with levels in controls. In contrast, mRNA levels for TIMP-1 and TIMP-2 increased significantly at 24 wk after streptozotocin injection (TIMP-1: 8.0-fold (P < 0.01) and TIMP-2: 6.4-fold (P < 0.01)). Enalapril attenuated the increases in mRNA levels for (alpha 1(IV) collagen chain (P < 0.01), laminin B1 (P < 0.01) and B2 chains (P < 0.01), and alpha 1(I) (P < 0.01) and alpha 1(III) (P < 0.01) collagen chains that are observed in the glomeruli of diabetic rats, but it had no effect on decreased mRNA levels for MMP-1 and MMP-3 or increased mRNA levels for TIMP-1 and TIMP-2. These data suggest that enalapril therapy may be effective in reducing mRNA expression for ECM components in diabetic glomeruli and that the mechanism underlying the abnormal regulation of mRNA for ECM components and MMP/TIMP may be different in diabetic glomeruli.