Alleviation of Oral Exposure to Aflatoxin B1-Induced Renal Dysfunction, Oxidative Stress, and Cell Apoptosis in Mice Kidney by Curcumin

Abstract

Aflatoxin B1 is a contaminant widely found in food and livestock feed, posing a major threat to human and animal health. Recently, much attention from the pharmaceutical and food industries has been focused on curcumin due to its strong antioxidant capacity. However, the therapeutic impacts and potential mechanisms of curcumin on kidney damage caused by AFB1 are still incomplete. In this study, AFB1 triggered renal injury in mice, as reflected by pathological changes and renal dysfunction. AFB1 induced renal oxidative stress and interfered with the Keap1–Nrf2 pathway and its downstream genes (CAT, SOD1, NQO1, GSS, GCLC, and GCLM), as manifested by elevated oxidative stress metabolites and reduced antioxidant enzymes activities. Additionally, AFB1 was found to increase apoptotic cells percentage in the kidney via the TUNEL assay, along with increased expression of Cyt-c, Bax, cleaved-Caspase-3, Caspase-9, and decreased expression of Bcl-2 at the transcriptional and protein levels; in contrast, for mice given curcumin, there was a significant reversal in kidney coefficient, biochemical parameters, pathological changes, and the expression of genes and proteins involved in oxidative stress and apoptosis. These results indicate that curcumin could antagonize oxidative stress and apoptosis to attenuate AFB1-induced kidney damage.

Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications

“…Additionally, several clinical studies have shown that curcumin has a strong therapeutic potential for treating a few chronic illnesses, including pulmonary, cancer, neurological, cardiovascular, infectious, neoplastic, psychiatric, and metabolic disorders [ 68 ]. Not surprisingly, several in vitro and animal experimental studies confirmed that curcumin supplementation could offer strong protective effects against AFB1-induced liver injury, mutagenicity, hepatocarcinogenicity, renal dysfunction, ileum damage, immune toxicity via regulating multiple above-mentioned targets [ 26 , 34 , 60 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. The detailed molecular pathways are discussed in the section below.…”

“…Oxidative stress is one of the critical molecular mechanisms of adverse effects caused by many toxic chemical hazards or drugs (e.g., heavy metals, mycotoxins, pesticides, chemotherapy drugs, and antibiotics) [ 88 ]. Multiple studies reported that AFB1 and its derivatives could trigger oxidative stress by inducing the formation of ROS or decreasing intracellular antioxidants or the activities of antioxidant enzymes [ 36 , 70 , 73 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. In the liver tissues, the cytochrome (CYP)1A2 and CYP3A4 could bio-transform into AFBO, which is a harmful and extremely active, electrophilic metabolite.…”

“…Wang et al discovered that oral administration of AFB1 at 750 μg/kg BW for 30 days might produce significant kidney oxidative damage, as demonstrated by the loss of antioxidative enzyme (e.g., CAT and SOD) activities and the decreases in GSH levels and increases in hydrogen peroxide (H 2 O 2 ) and levels of MDA in the kidney tissues; meanwhile, oral administration of curcumin supplementation could significantly inhibit AFB1-induced oxidative stress by upregulating the GSH content and SOD and CAT activities [ 70 ]. Consistently, curcumin supplementation could also significantly improve AFB1-exposure-induced cytotoxicity in bovine fetal hepatocyte-derived cells, renal damage in mice and chickens, and liver, spleen, and ileum damage in ducks by inhibiting the production of ROS and oxidative stress through the upregulation of activities of antioxidant enzymes and levels of antioxidants or free radical scavenging [ 60 , 69 , 70 , 72 , 74 , 75 ]. Very recently, Damiano et al found that curcumin supplementation significantly inhibits the expression of NADPH Oxidase 4 (NOX4) mRNA and protein, thus inhibiting AFB1-induced renal oxidative stress in chicken [ 75 ].…”

“…Under stressed environments, however, the ability of CULLIN3 to ubiquitinate Nrf2 is suppressed, which allows Nrf2 to be transcribed into the nucleus, inducing the expression of the protective genes in response to various stresses [ 106 ]. AFB1 exposure inhibited the expression of Nrf2 and its downstream proteins, including heme oxygenase-1 (HO-1), quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase catalytic subunit (GCLC), causing oxidative stress, liver damage, and nephrotoxicity in mice and broiler chicks [ 48 , 70 , 95 ]. It is well documented that curcumin is an inducer of Nrf2 [ 107 ].…”

“…Curcumin could directly bind to the cysteine 151 (Cys151) site of Keap1 protein and promote the liberation of Nrf2 [ 107 ]. Curcumin supplementation may greatly increase the expression and transcriptional activity of Nrf2, therefore reducing AFB1-induced tissue damage in the liver, kidney, and ileum [ 69 , 70 , 71 , 79 ]. Caveolin-1 is a major multifunctional scaffolding protein, and it could serve as a negative or positive modulator of cell signaling pathways, including PI3K/Akt and Nrf2 pathways [ 108 ].…”