Effect of a specific endothelin A receptor antagonist on murine lupus nephritis

Abstract

The present study was designed to assess whether a specific endothelin A (ET(A)) receptor antagonist, FR139317, affects the progression of lupus nephritis and affects transcription of mRNA for extracellular matrix (ECM) components metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP)-1, and accumulation of ECM proteins in the renal cortex of NZB/W F1 mice. mRNA levels for α1(I), α1(III), α1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-1, -2, -3, and TIMP-1 increased significantly as nephritis progressed in NZB/W F1 mice. At 48 weeks of age, the levels of mRNA for α1(I), α1(III), α1(IV) collagen chains, laminin B1 and B2 chains, HSPG, MMP-1, -2, -3, and TIMP-1 were increased by 5.6- (P < 0.001), 3.6- (P < 0.01), 6.8- (P < 0.001), 5.2- (P < 0.001), 5.0- (P < 0.001), 6.0- (P < 0.001), 7.6- (P < 0 001), 4.2- (P < 0.01), 8.2- (P < 0.001), and 15.2-fold (P < 0.001), respectively, in the renal cortex of NZB/W F1 mice compared to NZW mice. Immunofluorescence microscopy showed that the accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice increased markedly with the progression of nephritis. At 20 weeks of age, NZB/W F1 and NZW mice were divided into two groups that received either FR139317 or its vehicle (saline) intraperitoneally, daily, for 28 weeks. The development of histological lesions, proteinuria, hypertension accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice were suppressed by FR139317 treatment. Levels of mRNA for ECM components, MMPs, and TIMP-1 in the renal cortex of NZB/W F1 mice were ameliorated significantly by FR139317 administration. There data suggest that FR139317 treatment can be used therapeutically to regulate the expression of ECM components, MMps, and TIMP-1 in murine lupus nephritis.