PDTC attenuate LPS-induced kidney injury in systemic lupus erythematosus-prone MRL/lpr mice.

Lipopolysaccharide (LPS) from bacteria can accelerate and exacerbate lupus nephritis (LN) and induce infiltrating inflammatory cells in kidney in animal models. Pyrrolidine dithiocarbamate (PDTC) is known to exert anti-inflammatory effects. Monocyte chemoattractant protein-1(MCP-1) is upregulated by various stimuli, including LPS, high glucose, and hyperosmolality. However, the molecular mechanisms of transcriptional regulation of the MCP-1 protein expression with LPS are poorly understood. Expression of MCP-1 was examined by western blot and enzyme-linked immunosorbent assay, respectively. The activity of nuclear factor (NF)-kappaB was measured by western blot. These mice have uncontrolled proliferation of T cells, an impaired response to T cell mitogen and produce autoantibodies against nuclear antigens, including DNA. We found that after LPS treatment for 14 weeks, LPS increased MCP-1 protein expression in kidney, which was significantly suppressed by antioxidant PDTC. The expression of NF-κB, pERK, pJNK and MCP-1 were increased, pp38 expression was decreased significantly, concomitantly with sera anti-dsDNA, MCP-1 and the acceleration of severity of autoimmune kidney injury. LPS induce markedly neutrophil infiltration in the glomerulus, especially around the mesangial region. PDTC reduced the number of infiltrating inflammatory cells and severity of kidney injury via inhibiting NF-κB and p38 MAPK activity. They also markedly prevented LPS-induced pJNK and MCP-1. Therefore, MCP-1 may be responsible for the recruitment and activation of leukocytes in diseased kidneys in female MRL/lpr mice. In this study, the long-term administration of PDTC had impacts on the prevention of end-stage organ damage induced by LPS treated. We demonstrated that PDTC inhibited LPS-induced monocyte migration and attenuated LPS-induced p38 MAPK activation. Based on these data we infer that PDTC inhibits LPS-induced MCP-1 expression, secretion and function through inhibition of NF-κB and p38 MAPK activity. Our study suggests that MAPK is an important therapeutic target of monocyte recruitment and accumulation within the glomerulus in inflammatory renal disease. These results suggest that PDTC protects against kidney inflammation of SLE at least in part via NF-κB and MAPK signaling pathways induction, and that inhibitory action on anti-dsDNA may be associated with the protective mechanism of PDTC. In summary, PDTC pretreatment attenuates LPS-induced kidney injury in female MRL/lpr mice through regulating NF-κB and MAPK signaling pathways. Our results indicate that LPS induces MCP-1 mainly through activating NF-κB and its downstream MAPK, and that such effect was inhibited by PDTC, suggesting the efficacy of PDTC in preventing kidney fibrosis in lupus-prone mice. Therefore, appropriate inhibition of NF-κB activation may attenuate the kidney injury in lupus-prone mice.