Effects of ochratoxin A on ER stress, MAPK signaling pathway and autophagy of kidney and spleen in pigs

Abstract

Ochratoxin A (OTA), a worldwide mycotoxin found in food and feeds, is a potent nephrotoxin and immunotoxin in animals and humans. This research was conducted to evaluate whether endoplasmic reticulum (ER) stress, MAPK signaling pathway and autophagy were induced by OTA in kidney and spleen of pigs. Twenty-seven crossbred pigs randomly allocated to 3 groups were fed for 42 days ad libitum a basal diet without (Con group, 0.00 μg OTA/kg) and with supplementation of OTA at 400 (OTA-L group) and 800 μg/kg (OTA-H group). From each group, 6 pigs were randomly selected for blood collection on days 0, 21, and 42 and 3 pigs were randomly selected for tissue collection on day 42. The results showed that OTA at 400 and 800 μg/kg diets significantly increased OTA concentrations in serum and kidney and spleen induced the histopathological lesions of kidney and spleen, decreased TCR-stimulated T lymphocyte viabilities and IL-2 concentration, increased TNF-α concentration, and decreased T-AOC levels. OTA increased glucose regulated protein 78, p38, and ERK1/2 phosphorylation, and LC3 II and Atg5 protein expression in kidney and spleen of pigs. These results provide new insights into the relationship between OTA and ER stress, p38 and ERK1/2 MAPK signaling pathway and autophagy in pigs.

Selenium Yeast Alleviates Ochratoxin A-Induced Hepatotoxicity via Modulation of the PI3K/AKT and Nrf2/Keap1 Signaling Pathways in Chickens

“…Nrf2, which is a major transcription factor in the antioxidant system and is involved in the regulation of antioxidant enzyme expression, is inhibited by Keap1 under physiological conditions [34,35]. Previous studies have shown that OTA toxicity is associated with oxidative stress [36], apoptosis [37], autophagic cell death [38], mitochondrial dysfunction and induction of mitochondrial biogenesis [39]. Studies have indicated that oxidative stress is a key determinant of OTA-induced toxicity [40,41].…”

Mycotoxins and oxidative stress: where are we?

“…Studies involving mammalian species in vitro (Bhat et al, 2016;Gayathri et al, 2015;Lautert et al, 2014; and in vivo (Aydin et al, 2003;Tanaka et al, 2016) showed nephrotoxic, hepatotoxic, immunotoxic, enterotoxic, neurotoxic and teratogenic effects of OTA. The toxicity and carcinogenic mechanisms of OTA have been associated with induction of oxidative stress (Costa et al, 2016), cell apoptosis (Ramyaa and Padma, 2013), cell autophagy/mitophagy (Gan et al, 2017;Qian et al, 2017) and protein synthesis inhibition (Mally and Dekant, 2009).…”

“…ROS generation has been reported to trigger OTA toxicity (Zhu et al, 2017). Several oxidative stress mechanisms elicited by OTA have been proposed through in vivo (Abdel-Wahhab et al, 2017;Gan et al, 2017) and in vitro studies (Bhat et al, 2016;Ramyaa et al, 2014) (Figure 1). OTA can cause damage due to oxidative stress through the generation of hydroxyl radicals via the Fenton reaction, via flavoprotein NADPH-cytochrome P450 activation and inhibition of Nrf2 activation and gene transcription.…”

Nontoxic concentration of ochratoxin A decreases the dosage of cyclosporine A to induce chronic nephropathy model via autophagy mediated by toll-like receptor 4

“…However, practice of CsA is restricted because of its side effects on heart, liver, and nervous system. The target organ of OTA is also kidney and several studies showed that OTA could cause renal injury in cells and animals 20,29 . And the dosage in our study is 0.25 mg/kg per day, which is nontoxic for mice.…”

“…The expression of transforming growth factor-beta1 (TGF-β1), excessive apoptosis, autophagy, and production of inflammatory factors could be upregulated in chronic CsA nephropathy 18 . OTA-induced nephropathy was related to them as well [19][20][21] . Among them, inflammation plays a vital role in the progression of renal diseases, in which toll-like receptor 4 (TLR4) represents a major component in innate immunity.…”