Central role of TRAP1 in the ameliorative effect of oleanolic acid on the mitochondrial-mediated and endoplasmic reticulum stress-excitated apoptosis induced by ochratoxin A

Abstract

Ochratoxin A (OTA) is a nephrotoxic mycotoxin that is widely distributed in foodstuffs and feeds, meanwhile oleanolic acid (OA) is ubiquitous in various fruit skins, food materials, and medicinal herbs. Due to that OA has a nephroprotective effect, it has the poteintial to counteract OTA-induced nephrotoxicity by nutritional intervention of OA. Furthermore, tumor necrosis factor receptor-associated protein 1 (TRAP1) acts as the core of endoplasmic reticulum (ER)-mitochondria crosstalk, becoming our focus in the mechanism investigation. In this study, the cell viability, apoptosis rate, and protein expressions of human proximal tubule epithelial-originated kidney-2 (HK-2) cells in response to OTA and/or OA were determined. Results indicated that a 24 h-treatment of 1-5 μM OTA could notably induce mitochondrial-mediated and ER stress (ERS)-excitated apoptosis via inhibiting TRAP1, thereby activating CypD, Bax, Cyt-C, Cleaved Caspase-9, Cleaved Caspase-3, GRP78, p-PERK, p-eIF2α, ATF4, and CHOP and inhibiting Bcl-2 (P < 0.05). Results of the RNA interference of TRAP1 further ascertained its anti-apoptotic function via inhibiting CypD, Bax, GRP78, and CHOP and enhancing Bcl-2 (P < 0.05). The pre-treatment of 2 μM OA for 2 h could remarkably relieve OTA-induced suppression of TRAP1 (P < 0.05). In conclusion, TRAP1 played a central role in the ameliorative effect of OA on the mitochondrial-mediated and ERS-excitated apoptosis induced by OTA.

Keywords: ER-mitochondria crosstalk; Mycotoxin; Oleanolic acid; Protein homeostasis; Tumor necrosis factor receptor-associated protein 1.