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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.

The farnesoid X receptor (FXR) is mainly expressed in liver, intestine and kidney. We investigated whether 6-ethyl chenodeoxycholic acid (6ECDCA), a semisynthetic derivative of chenodeoxycholic aicd (CDCA, an FXR ligand), protects against kidney injury and modulates small heterodimer partner (SHP) in cisplatin-induced kidney injury. Cisplatin inhibited SHP protein expression in the kidney of cisplatin-treated mice and human proximal tubular (HK2) cells; this effect was counteracted by FXR ligand. Hematoxylin and eosin staining revealed the presence of tubular casts, obstructions and dilatations in cisplatin-induced kidney injury, which was attenuated by FXR ligand. FXR ligand also attenuated protein expression of transforming growth factor-β1 (TGF-β1), Smad signaling, and the epithelial-to-mesenchymal transition process, inflammatory markers and cytokines, and apoptotic markers in cisplatin-treated mice. Cisplatin induced NF-κB activation in HK2 cell; this effect was attenuated by pretreatment with FXR ligand. In SHP knockdown by small interfering RNA, cisplatin-induced activation of TGF-β1, p-JNK and Bax/Bcl-2 ratio was not attenuated, while SHP overexpression and FXR ligand inhibited expression of these proteins in cisplatin-pretreated HK2 cells. In conclusion, FXR ligand, 6ECDCA prevents cisplatin-induced kidney injury, the underlying mechanism of which may be associated with anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through SHP induction.

Background: Cisplatin-induced nephropathy has been related to increased lipid peroxide formation and decreased activity of antioxidant enzymes in the kidney. The present study aimed to examine whether treatment with alpha-lipoic acid (alpha-LA) prevents the cisplatin-induced nephrotoxicity., Methods: Two groups of rats were treated with cisplatin, one of which being cotreated with alpha-LA. The control group was treated with vehicle only. Four days later, the expression of aquaporins and sodium transporters was determined in the kidney by immunoblotting and immunohistochemistry. The arginine vasopressin-stimulated generation of cAMP was measured by radioimmunoassay. The expression of nitric oxide synthases (NOS) was determined by immunoblotting. The mRNA expression of endothelin-1 (ET-1) and tumour necrosis factor (TNF)-alpha was measured by real-time PCR. Apoptosis was examined by TUNEL staining., Results: Following the treatment with cisplatin, urinary volume and fractional excretion of sodium increased. Accordingly, the expression of aquaporins 1-3, Na,K-ATPase, NHE3 and NKCC2 was decreased. The expression of adenylyl cyclase VI and vasopressin-stimulated cAMP generation was decreased. The expression of inducible NOS was increased, while that of endothelial NOS decreased. The ET-1 expression was increased. TUNEL-positive cells were increased, in association with an increased expression of TNF-alpha. alpha-LA treatment prevented dysregulation of these parameters and resumed the renal function., Conclusion: alpha-LA may prevent the cisplatin-induced nephrotoxicity, possibly through preserving the activities of NO and ET systems and inhibiting the development of apoptosis.