Role of reactive oxygen species in triptolide-induced apoptosis of renal tubular cells and renal injury in rats

Abstract

This study investigated the role of reactive oxygen species (ROS) in the pathogenesis of triptolide-induced renal injury in vivo. Rats were randomly divided into 4 groups (n=5 in each): triptolide group in which the rats were intraperitoneally injected with triptolide solution at a dose of 1 mg/kg of body weight on day 8; control group in which the rats received a single intraperitoneal injection of 0.9% physiological saline on day 8; vitamin C group in which the rats were pretreated with vitamin C by gavage at a dose of 250 mg/kg of body weight per day for 7 days before the same treatment as the control group on day 8; triptolide+vitamin C group in which the rats were first subjected to an oral administration of vitamin C at a dose of 250 mg/kg of body weight per day for 7 days, and then to the same treatment as the triptolide group on day 8. All the rats were sacrificed on day 10. Blood samples were collected for detection of plasma creatinine (Pcr) and plasma urea nitrogen (PUN) concentrations. Both kidneys were removed. The histological changes were measured by haematoxylin-eosin (HE) staining. The production of ROS was determined by detecting the fluorescent intensity of the oxidation-sensitive probe rhodamine 123 in renal tissue. Renal malondialdehyde (MDA) content was measured to evaluate lipid peroxidation level in renal tissue. TUNEL staining was performed to assess apoptosis of renal tubular cells. Renal expression of apoptosis-related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding encoding genes were assessed by Western Blotting and real-time PCR. The results showed that triptolide treatment promoted the generation of a great amount of ROS, up-regulated the expression of Bax, Bid, Bad, Fas and FasL at both protein and mRNA levels, as well as the ratio of Bax to Bcl-2, and caused the apoptosis of renal tubular cells and renal injury. However, pretreatment with an antioxidant, vitamin C, significantly reduced the generation of ROS and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury. It was concluded that ROS plays a critical role in triptolide-induced apoptosis of renal tubular cells and renal injury. The protective administration of vitamin C may help alleviate triptolide-induced renal injury and nephrotoxicity.

Sphingolipids as New Biomarkers for Assessment of Delayed-Type Hypersensitivity and Response to Triptolide

“…In previously studies, DTH and improper dose of triptolide could cause significant kidney dysfunction [16], [43], [44]. Thus, as described above in this study, the down-regulation of sphingolipid levels might correlate with the exacerbation of kidney dysfunction.…”

“…Thus, both DTH induced by DNFB and treatment with triptolide have harmful effects on the kidney. Many previous studies have shown the deleterious effects of triptolide on kidney function; TWHF was toxic to rodent kidneys even at normal dosage levels [15], [16], [44]–[46]. These early studies reported that oxidative stress caused by triptolide is involved in drug-induced nephrotoxicity by reducing the activity of renal superoxide dismutase and glutathione peroxidase and increasing renal malondialdehyde content [16], [44].…”

“…Many previous studies have shown the deleterious effects of triptolide on kidney function; TWHF was toxic to rodent kidneys even at normal dosage levels [15], [16], [44]–[46]. These early studies reported that oxidative stress caused by triptolide is involved in drug-induced nephrotoxicity by reducing the activity of renal superoxide dismutase and glutathione peroxidase and increasing renal malondialdehyde content [16], [44]. However, although the accumulation of HexCer(d18∶1/16∶0) might be caused by the degradation of complex glycosphingolipids induced by triptolide, no connection between the nephrotoxic effects of triptolide and its effects on sphingolipid levels has been reported so far.…”

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

“…ABT % Inhibition of CYP3A by ABT Cytotoxicity without ABT Cytotoxicity with ABT (Shu et al, 2009;Yang et al, 2011). In the current study, it was confirmed that TP did upregulate the antiapoptosis protein Bax and downregulate the proapoptotic protein Bcl-2 in SCRH.…”

Lipid nanoparticles loading triptolide for transdermal delivery: mechanisms of penetration enhancement and transport properties

“…However, TPL rapidly reaches C max (10 min), distributes in the other organs and excreted (t 1/2 , 38 min) via biliary, urinary and fecal routes after oral administration [ 5 ]. The toxic and side effects on liver and spleen were reported frequently [ 6 , 7 ]. Thus, TPL formulation with better patient compliance and controlled release required more studies in novel drug delivery routes, including transdermal delivery.…”