Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity
Introduction
Although cisplatin is a highly effective anti-neoplastic agent, its nephrotoxicity is a major clinical problem. Nephrotoxicity by cisplatin occurs in a dose-dependent manner, is cumulative, and occurs to varying degrees in 25–35% of patients receiving a single dose of cisplatin (Ries and Klastersky, 1986, Saleh and El-Demerdash, 2005). Cisplatin-induced nephrotoxicity can result in severe renal tubular injury leading to acute renal failure (Kang et al., 2004). Cisplatin causes tubular injury through multiple mechanisms, including hypoxia, the generation of free radicals, inflammation, and apoptosis. Cisplatin-induced nephrotoxicity was shown to be associated with an increase in the pro-apoptotic protein Bax and a decrease in the anti-apoptotic protein Bcl-2 (Tsuruya et al., 2003). Additionally, significant interactions among these various pathways may occur in cisplatin injury (Engineer et al., 1989, Yao et al., 2007). In particular, nitric oxide (NO) has been suggested to play an important role in cisplatin-induced nephrotoxicity. l-Arginine, the precursor of NO in the body, attenuates cisplatin-induced nephrotoxicity, and a competitive inhibitor of NO synthase, NG-nitro-l-arginine methyl ester hydrochloride (l-NAME), exacerbates cisplatin-induced nephrotoxicity (Palmer et al., 1988, Saleh and El-Demerdash, 2005).
Sildenafil is a selective inhibitor of phosphodiesterase-5 (PDE5), which degrades cyclic guanosine monophosphate (cGMP), a downstream product in the NO–soluble guanylate cyclase cascade, in endothelial cells. NO is synthesized by three isoforms of NO synthase (NOS), i.e., neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS), all of which can be expressed in the kidney (Kone, 2004). Interestingly, sildenafil can induce iNOS and eNOS, and sildenafil-induced increases in NO have been associated with attenuation of doxorubicin-induced cardiotoxicity (Ockaili et al., 2002). Recently, several studies have shown that, in addition to treating erectile dysfunction, sildenafil can prevent or decrease tissue injury. In vivo and in vitro, early treatment with sildenafil ameliorated the progression of renal damage in the “5/6 nephrectomy” model (Rodriguez-Iturbe et al., 2005), and sildenafil has been reported to provide cardioprotection against ischemic injury when infused at the onset of reperfusion in rabbits (Das et al., 2004). In addition, sildenafil was found to reduce the hypertrophic response to isoprenaline in rat hearts (Fisher et al., 2005).
Owing to these effects of sildenafil, we hypothesized that sildenafil would attenuate cisplatin-induced nephrotoxicity. Here, we report that sildenafil decreases cisplatin-induced nephrotoxicity and present potential mechanism(s) involved in sildenafil-mediated protection.
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Animals and drug treatment
All experiments were performed on 8-week-old, male Sprague–Dawley (SD) rats weighing 250–260 g (Samtako, Kyoung Gi-Do, Korea). Rats were given a standard laboratory diet and water, and were cared for under a protocol approved by the Institutional Animal Care and Use Committee of the Chungnam National University Medical School. We divided the rats into five groups: untreated rats (n = 7), sildenafil-treated rats (n = 7), cisplatin-injected rats (n = 12), sildenafil-treated cisplatin-injected rats (n =
Effect of sildenafil on renal function
Blood urea nitrogen (BUN) and serum creatinine levels increased significantly in the vehicle + cisplatin-treated group. In contrast, intraperitoneal injection of sildenafil in cisplatin-treated rats significantly reduced the serum creatinine level compared with that in vehicle + cisplatin-treated rats (P < 0.05). l-NAME treatment reversed the effect of sildenafil (Fig. 1).
Effect of sildenafil on renal histology
Histological examination revealed brush border loss, vacuolation, and desquamation of epithelial cells in renal tubular epithelium
Discussion
In this study, we show that sildenafil attenuated cisplatin-induced nephrotoxicity, thereby reducing renal tubular damage, decreasing apoptosis, and suppressing serum BUN and creatinine levels. These effects were primarily attributable to the inhibition of apoptosis, as demonstrated by our findings that sildenafil treatment increased iNOS/eNOS and Bcl-2 expression and decreased the activation of caspase-3, the number of TUNEL-positive cells, and the expression of Bax.
Cisplatin-induced
Conflict of interest
The authors declare that there is no conflict of interest.
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