title: Grape seed proanthocyanidin extract protects from cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis.
abstract: Cisplatin (CP) is used as an antineoplastic drug in the clinic, but its nephrotoxicity limits its use. Grape seed proanthocyanidin extract (GSPE) is a powerful antioxidant. In this study, we investigated whether GSPE can prevent CP-induced nephrotoxicity and explored the underlying mechanism. Male C57/BL6 mice were randomly divided into four groups: control group (N), CP group (C), receiving an intraperitoneal (ip) injection of 20 mg/kg CP, GSPE group (G), receiving an intragastric (ig) dose of 500 mg/kg GSPE, and CP+GSPE group (C+G), where ig administration of GSPE was performed 30 min prior to ip injection of CP, followed by an additional ig administration of GSPE 72 h later. Blood and kidney samples were collected 120 h after treatment. The pathological changes in the kidney were examined by periodic acid-Schiff (PAS) staining, while the protein levels of glucose-regulated protein 78 (GRP78), phosphorylated‑extracellular signal-regulated kinase (p-ERK) and caspase-12 were examined by western blotting and immunohistochemical staining. Apoptosis was examined by a terminal deoxynucleotidyl transferase dUTP nick‑end labeling (TUNEL) assay. Compared to the CP group, the CP+GSPE group had a significant decrease in the level of blood urea nitrogen (BUN), serum creatinine (Scr) and reduced renal index (RI) (P<0.05), and showed limited histopathological damage. The number of TUNEL-positive cells was significantly reduced in the CP+GSPE group compared to the CP group (P<0.05), and the protein expression of GRP78, p-ERK and caspase-12 was significantly reduced in the CP+GSPE group (P<0.05). We conclude that GSPE can protect the renal function from CP-induced nephrotoxicity and can attenuate the endoplasmic reticulum (ER) stress‑induced apoptosis via regulation of the caspase-12 pathway.
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Guangyi
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Bei
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Nephrology, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Li
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001806:Blood Urea Nitrogen; D053454:Caspase 12 / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056604:Grape Seed Extract / Q000737:chemistry / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D044945:Proanthocyanidins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D044945:Proanthocyanidins; D003404:Creatinine; D048049:Extracellular Signal-Regulated MAP Kinases; D053454:Caspase 12; D002945:Cisplatin