ABSTRACT
BACKGROUND: Toll-like receptors recognize pattern-associated molecules found in pathogens as well as in endogen cells and in matrix degradation products. Despite the effectiveness of cisplatin against various solid tumors the administered dose is limited by its nephrotoxicity, namely, induction of tubular cell apoptosis. Herein, we investigated whether the cell toxicity of cisplatin was mediated by toll-like receptor 4 signaling. METHODS: C3H/He J (Toll-like receptor 4 deficient) and C3H/HePas (control) were treated with cisplatin (20 mg/kg). We evaluated renal function as well as expression of (HO-1) heme oxygenase 1 and MCP-1 mRNAs. RESULTS: Animals deficient in Toll-like receptor 4 showed less renal dysfunction after cisplatin therapy, which was more evident at later time points. Moreover, MCP-1 mRNA expression in kidneys from these animals were lower than controls, mainly at 96 hours after treatment. No differences were seen in HO-1 mRNA expression. CONCLUSIONS: These results suggested that cisplatin-induced renal toxicity is mediated in part though toll-like receptor 4.
Subject(s)
Cisplatin/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/physiopathology , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/physiology , Animals , Chemokine CCL2/genetics , Heme Oxygenase-1/genetics , Kidney Function Tests , Mice , Mice, Inbred C3H , Mice, Knockout , RNA, Messenger/geneticsABSTRACT
Ischemia and reperfusion injury (IRI) is the main etiology of acute renal failure in native and transplanted kidneys. In the transplantation field, immunosuppressive drugs may play an additional role in acute graft dysfunction. Rapamycin may impair renal regeneration post IRI. Heme oxygenase 1 (HO-1) is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in rapamycin-induced renal dysfunction in an established model of IRI. Rapamycin (3 mg/kg) was administered to mice before being subjected to 45 min of ischemia. Animals subjected to IRI presented with impaired renal function that peaked at 24 h (2.05+/-0.23 mg/dl), decreasing thereafter. Treatment with rapamycin caused even more renal dysfunctions (2.30+/-0.33 mg/dl), sustained up to 120 h after reperfusion (1.54+/-0.4 mg/dl), when compared to the control (0.63+/-0.09 mg/dl, P<0.05). Rapamycin delayed tubular regeneration that was normally higher in the control group at day 5 (68.53+/-2.30 vs 43.63+/-3.11%, P<0.05). HO-1 was markedly upregulated after IRI and its expression was even enhanced by rapamycin (1.32-fold). However, prior induction of HO-1 by cobalt protoporphyrin improved the renal dysfunction imposed by rapamycin, mostly at later time points. These results demonstrated that rapamycin used in ischemic-injured organs could also negatively affect post-transplantation recovery. Modulation of HO-1 expression may represent a feasible approach to limit rapamycin acute toxicity.