title: DPP-4 inhibitor attenuates toxic effects of indoxyl sulfate on kidney tubular cells.
abstract: Diabetic nephropathy is a common causative factor of chronic kidney disease (CKD). DPP-4 inhibitor has the ability to improve kidney function and renal microvasculature. In the present study, we investigate the deleterious effects of IS on proximal tubular cells and the protective role of DPP-4 inhibitor. Human kidney 2 (HK-2) cells were exposed to IS in the presence or absence of DPP-4 inhibitor. Effects of DPP-4 inhibitor on viability of HK-2 cells were determined by MTT assay. Reactive oxygen species (ROS) production was examined using fluorescent microscopy. Levels of cleaved caspase-3, transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA) and NF-kappaB p65 and phosphorylation of AKT and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. Production of ROS and level of cleaved caspase-3 were increased by IS in a dose-dependent manner. The phosphorylation of AKT and ERK p65 were decreased alongside activation of NF-κB. Expression of TGF-β and α-SMA, were upregulated in IS-treated HK-2 cells. Treatment with DPP-4 inhibitor resulted in a significant increase in cell viability and a decrease of ROS production in IS-treated HK-2 cells. DPP-4 inhibitor restored IS-induced deactivations of AKT and ERK and inhibited activation of NF-κB in IS-treated HK-2 cells. Moreover, DPP-4 inhibitor could also attenuate IS-induced up-regulation of TGF-β and α-SMA expression. These findings suggest that DPP-4 inhibitor possesses anti-apoptotic activity to ameliorate the IS-induced renal damage, which may be partly attributed to regulating ROS/p38MAPK/ERK and PI3K-AKT pathways as well as downstream NF-κB signaling pathway.
authors.affiliation: Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, Taiwan; Division of Nephrology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Healthy and Welfare, Taoyuan, Taiwan.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Taoyuan General Hospital, Ministry of Healthy and Welfare, Taoyuan, Taiwan.
authors.forename: Chen-Hung
authors.initials: CH
authors.lastname: Chang
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Acupuncture, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Mao-Feng
authors.initials: MF
authors.lastname: Sun
authors.affiliation: Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Acupuncture, China Medical University Hospital, Taipei Branch, Taiwan.
authors.forename: Sheng-Feng
authors.initials: SF
authors.lastname: Hsu
authors.affiliation: Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, Taiwan; Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ching-Sung
authors.initials: CS
authors.lastname: Weng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D007200:Indican / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D007200:Indican
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