Boldine provides protective effect against nephrotoxicity induced by cisplatin in Wistar rats:Role of oxidative stress,inflammation and caspase-3

Side effects of cisplatin,especially dose-dependent nephrotoxicity,are major factors limiting its use in cancer.Boldine((S)-2,9-dihydroxy-1,10-dimethoxy-aporphine)is a natural alkaloid known for its strong antioxidant activity present in leaves/bark of boldo tree(Peumus boldus Molina),a native tree in Chile.Here,we aimed to investigate the nephroprotective effect of boldine and its underlying mechanisms on cisplatin-induced rat renal injury.Thirty Wistar albino rats divided into 5 groups(Control,Cis,Bold.40,Cis+Bold.20,Cis+Bold.40 groups)were used.Rats received boldine(20 or 40 mg/kg/day),or vehicle(saline)intraperitoneal for 14 days and a single dose cisplatin(7 mg/kg,ip)was applied on the 10th day to induce nephrotoxicity.Rats and kidney tissue were weighed to determine kidney index.Blood urea nitrojen(BUN)and creatinine levels,the amount of thiobarbituric acid reactive substances(TBARS,an index of lipid peroxidation),superoxide dismutase(SOD),glutathione peroxidase(GPx)enzyme activities and tumor necrosis factor alpha(TNF-α)levels were measured and histopathologic examination was performed.Inducible nitric oxide synthase(iNOS)and caspase-3 expressions were detected immunohistochemically.Nephrotoxicity induced by cisplatin was apparent by elevated levels of BUN,creatinine,kidney index,TBARS and TNF-α,and decreased body weight,SOD and GPx enzyme levels.Pretreatment with boldine protected the renal function at both boldine doses by fixing the renal damage markers,oxidative stress,caspase-3 and iNOS expression.Histopathological findings supported biochemical findings.Taken together these findings indicate that boldine has promising protective effect against cisplatin nephrotoxicity by improving oxidative stress,inflammation,histopathological alterations and by alleviating caspase 3 expression.

Ameliorative Effect of Ginsenoside RT-5 on CDDP-Induced Nephrotoxicity

The aim of this study is to explore whether RT-5, one novel active ginsenosides from Ginseng, has protective effects against cisplatin（CDDP）-induced nephrotoxicity in vivo. One model of acute renal failure induced by CDDP in rats and one model of xenograft tumors of human cervical cancer in nude mice are established. Four groups are assigned： control, CDDP, RT-5, CDDP plus RT-5, in which the RT-5 is administered via oral gavage 24 h before CDDP intraperitoneal injection. The significant increase in blood urea nitrogen and creatinine are induced by CDDP treatment at 6 mg/kg, which are attenuated by pre-treated with RT-5 at 10 mg/kg. RT-5 could ameliorate CDDP-induced morphological damages in kidney by PAS staining, and reduce tubular apoptosis evaluated by TUNEL staining. Pretreatment with RT-5 notably inhibits CDDP-induced oxidative stress in kidney tissues. Interestingly, RT-5 does not interfere with the in vivo anti-cancer effects of CDDP against the growth of xenograft tumors in nude mice. These data suggest that co-treatment RT-5 with CDDP might attenuate the following nephrotoxicity without inhibiting its anti-tumor efficiency, which could provide one novel strategy for cancer treatment in clinics.

Plasmacytoid dendritic cells promote acute kidney injury by producing interferon-α

Acute kidney injury(AKI)is a common clinical complication associated with high mortality in patients.Immune cells and cytokines have recently been described to play essential roles in AKI pathogenesis.Plasmacytoid dendritic cells(pDCs)are a unique DC subset that specializes in type Ⅰ interferon(IFN)production.Here,we showed that pDCs rapidly infiltrated the kidney in response to AKI and contributed to kidney damage by producing IFN-α.Deletion of pDCs using DTR^(BDCA2) transgenic(Tg)mice suppressed cisplatin-induced AKI,accompanied by marked reductions in proinflammatory cytokine production,immune cell infiltration and apoptosis in the kidney.In contrast,adoptive transfer of pDCs during AKI exacerbated kidney damage.We further identified IFN-α as the key factor that mediated the functions of pDCs during AKI,as IFN-α neutralization significantly attenuated kidney injury.Furthermore,IFN-α produced by pDCs directly induced the apoptosis of renal tubular epithelial cells(TECs)in vitro.In addition,our data demonstrated that apoptotic TECs induced the activation of pDCs,which was inhibited in the presence of an apoptosis inhibitor.Furthermore,similar deleterious effects of pDCs were observed in an ischemia reperfusion(IR)-induced AKI model.Clinically,increased expression of IFN-α in kidney biopsies was observed in kidney transplants with AKI.Taken together,the results of our study reveal that pDCs play a detrimental role in AKI via IFN-α.