Segment-specific proximal tubule injury in tripterygium glycosides intoxicated rats

Tripterygium glycosides (TG), extracted from the Chinese herb Tripterygium wilfordii Hook. f, is a widely used anti-inflammatory and immunosuppressive agent with definite nephrotoxicity. However, its toxic mechanism remained undiscovered. The aim of this study was to characterize the potential toxicity of TG on segments of proximal tubule in rats. Six hundred and 1200 mg/kg of TG was administered by daily intragastric instillation for 16 days. A significant reduction of p-aminohippurate accumulation by renal cortical slices indicated that TG damaged organic anion transporter (OAT) system that localized at the proximal tubule, especially S(2) segment. A dramatic loss of kidney glutamine synthetase (GS) activity induced by TG reflected S(3) segment damage. Because mRNA expression of OAT1, OAT3, and GS was decreased substantially, we ascribe the fall of p-aminohippurate accumulation and GS activity to alterations at the transcriptional level. A dose-related diminution of kidney glutathione S-transferase activity was noted simultaneously, suggesting oxidative stress involvement. Histopathological lesions were observed in the TG intoxicated rat kidney even though there were no obvious changes of serum urea and creatinine at this dose level. In summary, we provided evidences supporting that TG caused segment-specific dysfunction in the kidney proximal tubule.