Abstract
Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP), water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1) also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.
Highlights
Cisplatin is an inorganic platinum compound with broad-spectrum anti-neoplastic activity against different types of human tumors, solid tumors
To investigate the effect of metalloporphyrins (FeTMPyP and Mn(III) tetrakis-(4-benzoic acid)-porphyrin (MnTBAP)) on cisplatin-induced renal dysfunction, levels of blood urea nitrogen (BUN) (Blood Urea Nitrogen) and creatinine were measured at 72 h after cisplatin administration in the mice serum
We demonstrated that two hours pretreatments with metalloporphyrins Fe(III) tetra-(N-methyl-49-pyridyl)-porphyrin (FeTMPyP) and MnTBAP attenuated cisplatin-induced kidney injury by reducing cellular oxidative/nitrative stress, caspase 3 activity, DNA fragmentation and apoptosis
Summary
Cisplatin (cis-diammine-dichloro-platinum) is an inorganic platinum compound with broad-spectrum anti-neoplastic activity against different types of human tumors, solid tumors. Severe side effects of cisplatin such as nephrotoxicity, neurotoxicity, ototoxicity, greatly hamper its chemotherapeutic efficacy [1]. The exact mechanisms of the side effects induced by cisplatin are not clearly understood. It is known that oxidative stress, i.e., the production of reactive oxygen species (ROS) is implicated in the progression of certain side effects [2]. Nitric oxide plays important role in cisplatin induced nephrotoxicity [3] as well as other ROS species such as superoxide anion and hydrogen peroxide are involved [4,5]. If effected cells in kidney produce both nitric oxide and superoxide with cisplatin, peroxynitrite must exist [6]
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