Nitrooleic acid protects against cisplatin nephropathy: role of COX-2/mPGES-1/PGE2 cascade.

Haiping Wang,Meng Yang,Liang Xu,Zhanjun Jia,Jing Sun,Tianxin Yang,Rong Wang,Kezhou Yu,Bing Zhao

doi:10.1155/2015/293474

Abstract

Nitrooleic acid (OA-NO2) is an endogenous lipid product which has novel signaling properties, particularly the activation of peroxisome proliferator-activated receptors. The current study aimed to evaluate the protective effects of OA-NO2 against cisplatin-induced kidney injury in mice. Mice were pretreated with OA-NO2 for 48 h before cisplatin administration, and the cisplatin-caused nephrotoxicity was evaluated. After the cisplatin treatment (72 h), the vehicle-treated mice displayed renal dysfunction, as evidenced by the elevated plasma urea and creatinine, which was consistent with the histological damage, such as tubular necrosis, dilation, protein cast, and desquamation of epithelial cells. In contrast, the severity of the renal dysfunction and histological change were reduced in the OA-NO2 pretreated mice. The renal COX-2 and mPGES-1 mRNAs and their respective proteins expression, together with the renal PGE2 amounts, were induced by the cisplatin treatment, but their initiation was reduced by OA-NO2. Moreover, the circulating TNF-α, renal TNF-α, IL-1β, MCP-1, ICAM-1, and VACAM-1 mRNA levels were higher in the cisplatin-treated mice, compared with the controls, but they were attenuated in the OA-NO2 pretreatment group. In summary, the pretreatment with OA-NO2 remarkably ameliorated the cisplatin-induced kidney injury in mice, possibly via the inhibition of the inflammatory response, associated with the COX-2/mPGES-1/PGE2 cascade.

Highlights

Introduction cisDiamminedichloroplatinum is a highly effective antineoplastic DNA-alkylating agent, and the cisplatinbased combination chemotherapy regimens are currently used as the front-line therapy in the treatment of a number of cancer types: testicular cancer, cancer of the bladder, epithelial ovarian cancer, endometrial cancer, cancer of the head and neck, ovarian germ cell tumors, advanced cervical cancer, mesothelioma, non-small-cell lung cancer [1], and so forth
Western blotting showed that the COX-2 protein content was elevated 23.1-fold three days after the cisplatin treatment, and the pretreatment with OA-NO2 diminished this induction (Figure 4)
It was determined that OA-NO2 inhibited the platelet aggregation, neutrophil activation, and nuclear factor κB-mediated cytokine release and stimulated the heme oxygenase- (HO-) 1 expression in different inflammatory conditions [8, 22]

Summary

Introduction

Introduction cisDiamminedichloroplatinum (cisplatin) is a highly effective antineoplastic DNA-alkylating agent, and the cisplatinbased combination chemotherapy regimens are currently used as the front-line therapy in the treatment of a number of cancer types: testicular cancer, cancer of the bladder, epithelial ovarian cancer, endometrial cancer, cancer of the head and neck, ovarian germ cell tumors, advanced cervical cancer, mesothelioma, non-small-cell lung cancer [1], and so forth. The therapeutic effects of cisplatin are significantly improved by its dose elevation. The high-dose therapy with cisplatin is limited by the emergence of serious adverse effects, nephrotoxicity [2], which is a frequent adverse result with about 25–35% patients suffering a decline in their renal functions after a single dose of cisplatin [3]. Hydration protocols were developed that reduced the nephrotoxicity and allowed an increase of the dose to achieve therapeutic levels [4]. Even with vigilant hydration, approximately one-third of the patients treated with cisplatin have a transient elevation of blood urea nitrogen levels or other evidence of kidney damage in the days following the cisplatin treatment [5]

Methods

Results

Conclusion