Renal protective roles of macrophage matrix metalloproteinase-12 in mice with obstructed kidneys

Abstract

Matrix metalloproteinase (MMP)-12 has been reported to have diverse functions, including regulation of immune reactions and anti-inflammatory effects, but the potential roles of MMP-12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP-12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP-12-deficient (MMP-12^−/−) mice and C57BL/6J mice as controls (MMP-12^+/+) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP-12 on monocytes/macrophages, we generated MMP-12-deficient, irradiated, chimeric mice (BM-MMP-12^−/−) and performed UUO. Bone marrow-derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP-12^−/− mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO-kidney compared with control mice. BM-MMP-12^−/− mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C⁺ macrophages in MMP-12^−/− mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]-1β, IL-6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP-12^−/− mice than in MMP-12^+/+ mice. MMP-12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation.