title: Activation of G-protein-coupled receptor 40 attenuates the cisplatin-induced apoptosis of human renal proximal tubule epithelial cells.
abstract: G-protein-coupled receptor 40 (GPR40) is known to play a role in the regulation of fatty acids, insulin secretion and inflammation. However, the pathophysiological roles of GPR40 in kidney disease have not yet been identified. In the present study, we investigated the expression of GPR40 during cisplatin-induced kidney injury using male Sprague-Dawley rats that were treated with 8 mg/kg cisplatin. Control rats were treated with saline. Following treatment with cisplatin, the protein expression of GPR40 in the kidneys was decreased in association with an increase in serum creatinine levels and the Bax/Bcl-2 expression ratio. To further investigate the function of GPR40, the human renal proximal tubule epithelial cell line (HK-2) was cultured with cisplatin in the absence or presence of GW9508, a selective GPR40 agonist. Pre-treatment of the HK-2 cells with GW9508 attenuated the decrease in cell viability induced by treatment with cisplatin. Treatment with cisplatin increased the number of cells with condensed nuclei, which was ameliorated by GW9508 pre-treatment. TUNEL assay also revealed that pre-treatment with GW9508 ameliorated cisplatin-induced apoptosis. Treatment with cisplatin increased the Bax/Bcl-2 expression ratio and cleaved caspase-3 expression, and promoted the activation of nuclear factor-κB (NF-κB). These changes were attenuated by pre-treatment with GW9508. The cisplatin-induced generation of reactive oxygen species (ROS) and the activation of the Src/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway were also counteracted by pre-treatment with GW9508. Thus, the activation of GPR40 attenuates cisplatin-induced apoptosis by inhibiting the generation of ROS, the activation of the Src/EGFR/ERK signaling pathway and the nuclear activation of NF-κB and pro-apoptotic factors.
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Seong Kwon
authors.initials: SK
authors.lastname: Ma
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Joo
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Hoon-In
authors.initials: HI
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Kwang Il
authors.initials: KI
authors.lastname: Nam
authors.affiliation: Department of Physiology, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Jongun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Soo Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013194:Staining and Labeling; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C473034:FFAR1 protein, human; C515630:GW9508; D008744:Methylamines; D016328:NF-kappa B; D011422:Propionates; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D051028:bcl-2-Associated X Protein; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin