#2349 Lysyl oxidase-like 2 inhibitor ameliorates tubulointerstitial fibrosis and albuminuria in cyclosporine induced nephropathy

Abstract

Abstract Background and Aims Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring in the tissue by facilitating collagen cross-linking. Recent data demonstrated upregulation of lysyl oxidase and LOXL2 in the fibrotic kidneys after administration of cylosporine A (CsA). Thus, inhibition of LOXL2 may render therapeutic effects against CsA-induced nephropathy by ameliorating tubulointerstitial fibrosis. Method Low salt fed CD-1 mice were administered saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. At 4 weeks, CsA-treated animals were divided into 2 groups respectively and treated with: (1) vehicle, (2) LOXL2 inhibitor (10 mg/kg/day, gavage feeding) for another 4 weeks up to 8 weeks. We explored the reduction of tubulointerstitial fibrosis as well as albuminuria with administration of LOXL2 inhibitor in CsA nephropathy mouse model. Results CsA administration significantly increased the levels of serum creatinine (10.0 ± 1.2 vs. 28.4 ± 4.3, p = 0.02), tubular injury scores (0.1 ± 0.2 vs. 3.6 ± 1.3, p = 0.03), tubulointerstitial fibrosis (Sirius red positive area, 14 ± 6% vs. 204 ± 43%, p = 0.01), F4/80 positive inflammatory cell infiltration in mouse kidney (2 ± 1 vs. 21 ± 4, p = 0.001). These changes were associated with upregulated mRNA expression of LOXL2, TGF-β1, and monocyte chemoattractant protein-1 (MCP-1). Administration of LOXL2 inhibitor significantly suppressed the expression of alpha-SMA and collagen 1A, intrarenal F4/80 positive inflammatory cell infiltrations (21 ± 4 vs. 14 ± 2, p = 0.001) and improved tubular injury scores (3.6 ± 1.3 vs. 1.6 ± 1.1, p = 0.02). Moreover, LOXL2 inhibitor effectively reduced albuminuria excretion (46 ± 4 vs. 22 ± 6, p = 0.02). Conclusion Our results suggest that LOXL2 inhibitor treatment can attenuate CsA nephropathy progression and LOXL2 may be a potential therapeutic target in CsA nephropathy.