The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy

Background. Macrophages play diverse roles in tissue injury. We evaluated their role in cyclosporine (CsA)-induced renal injury by depletion with liposomal clodronate (CL). Methods. Male Sprague Dawley rats were treated with CsA with or without CL treatment for 28 days. We assessed responses from the pathology and by measuring renal functions and levels of a proinflammatory cytokine (osteopontin), a profibrotic cytokine (βig-h3), innate immune response markers (toll-like receptor 2 and MHC class II molecules), apoptotic cell death (deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling staining and caspase-3 expression) and oxidative stress (8-hydroxy-2′-deoxyguanosine, 8-OHdG). Results. Macrophage depletion with CL improved not only renal function but also histopathology compared with the CsA-treated rats. Osteopontin and βig-h3 levels increased significantly in CsA-treated rat kidneys, but CL treatment decreased both markers. Enhanced innate immune response and apoptotic cell death in CsA-treated rat kidney were decreased with CL. The increased rates of urinary 8-OHdG excretion and the tubular expression of 8-OHdG produced by CsA treatment were reversed with CL treatment. Conclusions. Thus, infiltrating macrophages were involved in both nonimmunologic and immunologic injury and led to apoptotic cell death in this rat model of chronic CsA nephropathy.