The prophylactic protective effect of sesamol against ferric–nitrilotriacetate-induced acute renal injury in mice
Introduction
Nitrilotriacetic acid (NTA), a synthetic chelating agent, is used as a household and hospital detergent in various countries (Goddard and Sweeney, 1983, Hamazaki et al., 1985). NTA is a low-toxic agent (Hamazaki et al., 1985, Okada, 1996); however, the ferric–nitrilotriacetate (Fe–NTA) complex causes acute nephrotoxicity in animals and humans (Matsuura, 1983, Ebina et al., 1986). Although deferoxamine has been used to manage Fe–NTA intoxication, numerous side effects of deferoxamine chelation have been reported (Koren et al., 1989).
Oxidative-stress-associated lipid peroxidation (Suntres and Shek, 1996, Vega et al., 1998) is important in Fe–NTA-induced organ injury (Gutteridge, 1986, Kawabata et al., 1986, Iqbal et al., 2003, Hsu et al., 2006a, Hsu et al., 2007). Lipid peroxidation is one of the most investigated consequences of reactive oxygen substances on membrane structure and function; it is also involved in the development of tissue injury in various bio-systems (Freeman and Crapo, 1982). Recent studies (Bela et al., 2001, Motoyama et al., 2003, Lovat and Preiser, 2003) have confirmed increased systemic oxidative stress in patients with multiple organ injury. Furthermore, increased systemic oxidative stress is involved in the development of organ injury in iron-intoxicated patients (Agarwal et al., 2004). Hydroxyl radicals, an important toxic reactive oxygen species, are a prime initiator of oxidative stress and lipid peroxidation in organ injury (Umemura et al., 1996). Superoxide anion is important in generating hydroxyl radicals by reacting with hydrogen peroxide during iron intoxication (Emerit et al., 2001). Iron-induced reactive oxygen species originate from the interaction of iron with superoxide anion (Koppenol, 2001, Liochev and Fridovich, 2002). In addition, xanthine oxidase is a crucial enzyme in the generation of both superoxide anion and hydrogen peroxide (Pacher et al., 2006).
Sesame oil, derived from the plant species Sesamum indicum L., is used to increase resistance to lipid peroxidation and to protect against multiple organ injury (Hsu and Liu, 2004, Hsu et al., 2004). Sesame oil consists of various fatty acids and nonfat antioxidants, including 3,4-methylenedioxyphenol (sesamol). Sesamol decreases lipid peroxidation and protects against organ injury in a septic model (Hsu et al., 2006b, Hsu et al., 2006c). Although sesamol potently reduces oxidative stress and attenuates Fe–NTA-induced hepatocyte damage in vivo (Hsu et al., 2007) and ex vivo (Zhao et al., 1997), its effect on Fe–NTA-induced kidney injury is unclear. We examined the prophylactic protective effects of sesamol against Fe–NTA-induced acute renal injury in mice.
Section snippets
Materials
Sesamol, ferric nitrate, and NTA were bought from Sigma–Aldrich Co. (St. Louis, MO, USA). We prepared Fe–NTA solution from ferric nitrate and NTA (Uchida et al., 1996). Briefly, we mixed ferric nitrate with the disodium salt of NTA (1:4 w/w) in deionized water, and adjusted the pH to 7.4 using 1 M sodium bicarbonate solution. Fe–NTA intoxication is used for relevant animal models of acute iron intoxication (Zhang et al., 1996).
Animals
The animal care and experimental protocols were in accord with
Changes in serum BUN, creatinine, and CCr levels in Fe–NTA-treated mice
To select an optimal dose, we did a dose–response study of Fe–NTA on acute renal damage. Fe–NTA at a dose of 4 mg/kg significantly increased BUN, creatinine, and CCr levels compared to the control group (P < 0.05). Therefore, 4 mg/kg of Fe–NTA was used in the following experiments (Fig. 1).
Effects of sesamol on serum BUN, creatinine, and CCr levels in Fe–NTA-treated mice
To examine the prophylactic protective effect of sesamol on Fe–NTA-induced acute renal damage, serum BUN and creatinine concentrations and CCr levels were determined. Serum BUN and creatinine levels were
Discussion
In the present study, we focused on the prophylactic protective effect of sesamol on experimental Fe–NTA-induced renal injury, not hepatic injury, in mice. We showed that sesamol significantly attenuated Fe–NTA-induced renal injury, while our previous study (Hsu et al., 2007) focused on the protection of sesamol against Fe–NTA-induced hepatic injury. Some important differences between these two studies are these: (a) in our previous study (Hsu et al., 2007), we used 2 mg/kg of Fe–NTA to induce
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported by Grants NSC-96-2221-E-006-029-MY3, NSC-96-2314-B-006-012-MY2, and NSC-96-2628-B-006-038-MY3 from the National Science Council, Taiwan.
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