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Anti-Apoptotic Effect of G-Protein-Coupled Receptor 40 Activation on Tumor Necrosis Factor-α-Induced Injury of Rat Proximal Tubular Cells

Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Korea
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Int. J. Mol. Sci. 2019, 20(14), 3386; https://doi.org/10.3390/ijms20143386
Received: 21 June 2019 / Revised: 8 July 2019 / Accepted: 8 July 2019 / Published: 10 July 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic β-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway. View Full-Text
Keywords: G-protein-coupled receptor 40; apoptosis; tumor necrosis factor-alpha; angiotensin II type 1 receptor; ureteral obstruction; proximal kidney tubule G-protein-coupled receptor 40; apoptosis; tumor necrosis factor-alpha; angiotensin II type 1 receptor; ureteral obstruction; proximal kidney tubule
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Kim, C.S.; Joo, S.Y.; Kim, I.J.; Choi, H.-I.; Bae, E.H.; Kim, S.W.; Ma, S.K. Anti-Apoptotic Effect of G-Protein-Coupled Receptor 40 Activation on Tumor Necrosis Factor-α-Induced Injury of Rat Proximal Tubular Cells. Int. J. Mol. Sci. 2019, 20, 3386.

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