Role of endoplasmic reticulum stress in di(2-ethylhexyl) phthalate–induced renal toxicity and its amelioration by 4-phenylbutyric acid

Di (2-ethylhexyl) phthalate (DEHP) is an environmental toxicant which is commonly used as plasticizer in various plastic products. While the nephrotoxic potential of DEHP has been reported, the exact molecular mechanism behind DEHP-induced nephrotoxicity is still unexplored. This study aims to elucidate the specific role of ER stress in DEHP-induced nephrotoxicity and evaluate the targeted therapeutic potential of 4-Phenylbutyric acid (4-PBA), a chemical chaperone known to alleviate ER stress, against this toxicity. 24 Wistar albino rats were randomly divided into 4 groups (n = 6 each). In control group, corn oil was administered orally (p.o.) for 28 days. DEHP toxic group received DEHP (500 mg/kg, p.o., mixed in corn oil) for 28 days. In 4-PBA treatment groups, DEHP was administered for 28 days and afterwards 4-PBA co-treatment (500 mg/kg and 1000 mg/kg, p.o.) for last 14 days (day 15 to day 28) was given. On 29th day, rats were euthanized and blood as well as kidney samples were collected. Mechanistically, DEHP exposure resulted in severe renal dysfunction, evidenced by elevates levels of creatinine, urea, and BUN. At the molecular level, DEHP triggered significant oxido-nitrosative stress and upregulated the protein expression of key ER stress markers GRP78, CHOP, and Caspase 12, correlating with distorted renal histology. Notably, 4-PBA treatment significantly attenuated these biochemical and histological aberrations and downregulated protein expression of GRP78, CHOP, and Caspase 12. Our findings provide novel evidence that ER stress plays a crucial role in the development of DEHP-induced nephrotoxicity and 4-PBA has an ameliorative effect against it.