EFFECT OF A SPECIFIC ENDOTHELIN RECEPTOR-A ANTAGONIST AND AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR ON GLOMERULAR MESSENGER-RNA LEVELS FOREXTRACELLULAR-MATRIX COMPONENTS, METALLOPROTEINASES (MMP) AND A TISSUE INHIBITOR OF MMP IN AMINONUCLEOSIDE NEPHROSIS

Background. We previously reported that mRNA levels for extracellular matrix (ECM) components and endothelin (ET)-1 are upregulated in glome ruli of puromycin aminonucleoside (PAN) nephrosis. Angiotensin-convert ing enzyme (ACE) inhibitors are effective in experimental models of re nal injury, including PAN nephrosis. This study was designed to assess whether the glomerular expression of mRNA for ECM components, ET-1, m etalloproteinases (MMP), and a tissue inhibitor of metalloproteinases (TIMP) is modulated by a specific endothelin receptor A antagonist (FR 139317) or angiotensin- converting enzyme inhibitor (enalapril) in PAN -injected rats. Methods. Animals were divided into six groups. Group 1 consisted of PAN-injected rats given no treatment. In group 2, PAN-in jected rats were given enalapril 35 mg/l. In group 3, PAN-injected rat s were given an intraperitoneal injection of FRI39317. Group 4 consist ed of saline-injected rats given no treatment. In group 5, saline-inje cted rats were given enalapril. In group 6, saline-injected rats were given FR139317. We prepared glomerular RNA and performed Northern blot analysis in all groups. Results. In PAN nephrosis, glomerular mRNA le vels for alpha 1 (IV) collagen chain, laminin B1 and B2 chains, ET-1, MMP-2 and TIMP-1 increased at the peak of proteinuria on day s and the n decreased to the control level by day 20, whereas those for alpha 1 (I) and alpha 1 (III) collagen chains, MMP-1, MMP-3 and GAPDH showed l ittle change in PAN nephrosis throughout the experimental periods. In contrast, mRNA levels for heparan sulphate proteoglycan (HSPG) decreas ed on day 8 and then increased to the control level by day 20. Both en alapril and FR139317 attenuated the increases in mRNA levels for alpha 1 (IV) collagen chain (P < 0.01), laminin chains (P < 0.01), and ET-1 (P < 0.01), and attenuated the decreases in mRNA levels for HSPG (P < 0.01) in glomeruli of PAN-injected rats. Enalapril had little effect on increased glomerular mRNA levels for MMP-2 and TIMP-1 in PAN nephro sis, whereas FR139317 attenuated the increases in glomerular mRNA leve ls for MMP-2 (P < 0.01) and TIMP-1 (P < 0.01). Conclusions. These data suggest that the beneficial effects of enaIapril and FR139317 may be related to modulation of glomerular mRNA expression of ECM components and ET-1 and that these agents may follow a different mechanism in reg ulating the glomerular mRNA expression for MMP-2 and TIMP-1 in PAN nep hrosis.