Triptolide Improves Diabetic Nephropathy by Regulating Th Cell Balance and Macrophage Infiltration in Rat Models of Diabetic Nephropathy

Abstract

Objective: To investigate the therapeutic effect of triptolide (TP) on diabetic nephropathy (DN) in addition to its influence on helper T lymphocytes (Th) cells and monocytes/macrophages in rat models of DN.

Methods: Diabetes was induced in rats by feeding them high-fat diets and administering low-dose streptozotocin (STZ); subsequently, they were treated with TP (6, 12, or 24 mg/kg/day respectively) for 4 weeks. The general characteristics of the rats and their kidney weight to body weight ratio were observed. Liver and kidney function tests, routine blood tests, and 24 h urine protein tests were performed. Histological and ultrastructural pathologic changes in the kidneys were examined. Changes in the proportion of Th1/Th2 cells in peripheral blood and CD4⁺ T cells were measured. The serum levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10 were determined and the expression of these 4 cytokines in the kidneys was measured. Expression of the CD68 macrophage surface marker as well as that of phospho-nuclear factor kappa B (p-NF-κB), NF-κB, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, fibronectin (FN), IL-12, and signal transducer and activator of transcription-4 (STAT4) was evaluated in the kidneys.

Results: Elevated urine micro-albumin (UMA) and renal histological and ultrastructural changes were observed after the induction of diabetes. DN was associated with delayed immune-inflammatory responses induced by up-regulation of the proportion of Th1 cells and increase of the pro-inflammatory cytokines IFN-γ and TNF-α secreted by Th1 cells. In addition, down-regulation of the proportion of Th2 cells and decrease of the anti-inflammatory cytokines IL-4 and IL-10 secreted by Th2 cells were observed. TP could improve DN by regulating the Th1/Th2 cell balance. Macrophage infiltration as well as expression of inflammatory and pro-fibrogenic factors significantly increased in the kidneys of diabetic rats, which were suppressed by TP with the improvement in the medium-dose TP group (12 mg/kg/d) being the most significant.

Conclusion: TP can improve DN by regulating the Th1/Th2 cell balance and by reducing macrophage infiltration as well as the expression of relevant inflammatory factors in the kidney.

Key words

triptolide - diabetic nephropathy - macrophages - Th1/Th2 cells

^* Hang Guo and Congqing Pan contributed equally to this study.

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