RESUMEN
Accumulating data confirms that Methotrexate (MTX), a well-known immunosuppressive and anticancer drug, causes nephrotoxicity. Infliximab (INF), the inhibitor of tumor necrosis factor-alpha (TNF-α), was proven to have anti-inflammatory properties. Thus, it may have potential in preventing MTX-induced nephrotoxicity. Therefore, this study aimed to inspect the prospective nephroprotective effect of INF on MTX-induced rat nephrotoxicity through investigating the possible molecular mechanisms, including its interference with different death routes, oxidative stress as well as mitochondrial biogenesis. Rats received an INF intraperitoneal single dose of 7 mg/kg 72 h prior to a single 20 mg/kg MTX injection. MTX nephrotoxicity was demonstrated by significantly increased serum levels of the renal indicators urea and creatinine as well as renal inflammatory markers TNF-α and Interleukin-6 (IL-6) and the renal oxidative stress marker malondialdehyde (MDA), while renal antioxidant enzyme superoxide dismutase (SOD) was significantly decreased compared to control. INF injection prior to MTX markedly reversed these MTX-induced effects. Besides, MTX impaired mitochondrial biogenesis, while INF attenuated this impairment, as indicated by increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Finally, MTX triggered apoptotic and autophagic cascades in renal tissues as evidenced by reduced anti-apoptotic Bcl-2 protein expression as well as elevated expression of the pro-apoptotic protein Bax and both key regulators of autophagy; beclin-1 and LC-3, whereas INF pretreatment counteracted these apoptotic and autophagic effects of MTX. Summarily, these results suggest that INF provides protection against MTX-induced nephrotoxicity which could be elucidated by its antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagic effects as well as upregulating mitochondrial biogenesis.
Asunto(s)
Antioxidantes , Metotrexato , Ratas , Animales , Metotrexato/toxicidad , Antioxidantes/metabolismo , Infliximab/farmacología , Infliximab/uso terapéutico , Infliximab/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Biogénesis de Organelos , Estudios Prospectivos , Riñón/metabolismo , Estrés Oxidativo , Antiinflamatorios/farmacologíaRESUMEN
Methotrexate (MTX) is a chemotherapeutic agent used for treating several types of cancer as well as psoriasis and rheumatoid arthritis, but its use is limited due to its nephrotoxicity. The purpose of this research work was to observe ameliorative effects of L-carnitine (LC) toward renal toxicity caused by MTX and mechanisms responsible for these effects. Thirty-two male Sprague-Dawley rats were divided into four groups (eight rats/group), control group (received saline), MTX group (20 mg/kg/i.p. once), LC group (500 mg/kg/i.p. for 5 days), and MTX + LC group (received a single MTX dose 20 mg/kg/i.p. followed by LC 500 mg/kg/i.p. for 5 days). Histopathological examinations, lipid oxidation marker, malondialdehyde (MDA), and the antioxidant superoxide dismutase (SOD) as well as inflammatory (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]) and apoptotic markers (Bax, Bcl2, and caspase-3) were used to assess renal toxicity. Moreover, the protein levels of silent information regulator 1 (SIRT1) and its downstream signaling targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2) in addition to heme oxygenase-1 (HO-1) were measured. LC significantly protected against MTX-induced nephrotoxicity. It ameliorated MTX-induced renal histopathological changes and diminished MTX-induced renal oxidative stress, renal inflammation, and apoptosis. LC also upregulated the expression of SIRT1 and PGC-1 as well as Nrf2 and HO-1. By controlling the expression of renal SIRT1/PGC-1/Nrf2/HO-1, LC displayed antioxidant, anti-inflammatory, and anti-apoptotic activities. Hence, using LC supplements may help prevent negative MTX side effects.