scholarly journals Protective effects of dapagliflozin against oxidative stress-induced cell injury in human proximal tubular cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247234
Author(s):  
Nawel Zaibi ◽  
Pengyun Li ◽  
Shang-Zhong Xu
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Cell Injury ◽  
Ros Production ◽  
Protective Effects ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Mitochondrial Ros ◽  
Intracellular Ca ◽  
Proximal Tubular

Elevated reactive oxygen species (ROS) in type 2 diabetes cause cellular damage in many organs. Recently, the new class of glucose-lowering agents, SGLT-2 inhibitors, have been shown to reduce the risk of developing diabetic complications; however, the mechanisms of such beneficial effect are largely unknown. Here we aimed to investigate the effects of dapagliflozin on cell proliferation and cell death under oxidative stress conditions and explore its underlying mechanisms. Human proximal tubular cells (HK-2) were used. Cell growth and death were monitored by cell counting, water-soluble tetrazolium-1 (WST-1) and lactate dehydrogenase (LDH) assays, and flow cytometry. The cytosolic and mitochondrial (ROS) production was measured using fluorescent probes (H2DCFDA and MitoSOX) under normal and oxidative stress conditions mimicked by addition of H2O2. Intracellular Ca2+ dynamics was monitored by FlexStation 3 using cell-permeable Ca2+ dye Fura-PE3/AM. Dapagliflozin (0.1–10 μM) had no effect on HK-2 cell proliferation under normal conditions, but an inhibitory effect was seen at an extreme high concentration (100 μM). However, dapagliflozin at 0.1 to 5 μM showed remarkable protective effects against H2O2-induced cell injury via increasing the viable cell number at phase G0/G1. The elevated cytosolic and mitochondrial ROS under oxidative stress was significantly decreased by dapagliflozin. Dapagliflozin increased the basal intracellular [Ca2+]i in proximal tubular cells, but did not affect calcium release from endoplasmic reticulum and store-operated Ca2+ entry. The H2O2-sensitive TRPM2 channel seemed to be involved in the Ca2+ dynamics regulated by dapagliflozin. However, dapagliflozin had no direct effects on ORAI1, ORAI3, TRPC4 and TRPC5 channels. Our results suggest that dapagliflozin shows anti-oxidative properties by reducing cytosolic and mitochondrial ROS production and altering Ca2+ dynamics, and thus exerts its protective effects against cell damage under oxidative stress environment.

scholarly journals Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice

2020 ◽  
Vol 21 (11) ◽  
pp. 4054
Author(s):  
Kazuhiko Fukushima ◽  
Shinji Kitamura ◽  
Kenji Tsuji ◽  
Yizhen Sang ◽  
Jun Wada
Keyword(s):  
Renal Injury ◽  
Tubular Damage ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Renal Protection ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i–HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells

2011 ◽  
Vol 51 (6) ◽  
pp. 1258-1267 ◽  
Author(s):  
Tetsuro Koyama ◽  
Shinji Kume ◽  
Daisuke Koya ◽  
Shin-ichi Araki ◽  
Keiji Isshiki ◽  
...  
Keyword(s):  
Ros Production ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

scholarly journals Protein kinase C-α interaction with iHSP70 in mitochondria promotes recovery of mitochondrial function after injury in renal proximal tubular cells

2013 ◽  
Vol 305 (5) ◽  
pp. F764-F776 ◽  
Author(s):  
Grazyna Nowak ◽  
Sridharan Soundararajan ◽  
Ruben Mestril
Keyword(s):  
Mitochondrial Function ◽  
Ros Production ◽  
Atp Content ◽  
Oxidant Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Accelerated Proliferation ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

This study determined the role of PKC-α and associated inducible heat shock protein 70 (iHSP70) in the repair of mitochondrial function in renal proximal tubular cells (RPTCs) after oxidant injury. Wild-type PKC-α (wtPKC-α) and an inactive PKC-α [dominant negative dn; PKC-α] mutant were overexpressed in primary cultures of RPTCs, and iHSP70 levels and RPTC regeneration were assessed after treatment with the oxidant tert-butylhydroperoxide (TBHP). TBHP exposure increased ROS production and induced RPTC death, which was prevented by ferrostatin and necrostatin-1 but not by cyclosporin A. Overexpression of wtPKC-α maintained mitochondrial levels of active PKC-α, reduced cell death, and accelerated proliferation without altering ROS production in TBHP-injured RPTCs. In contrast, dnPKC-α blocked proliferation and monolayer regeneration. Coimmunoprecipitation and proteomic analysis demonstrated an association between inactive, but not active, PKC-α and iHSP70 in mitochondria. Mitochondrial iHSP70 levels increased as levels of active PKC-α decreased after injury. Overexpression of dnPKC-α augmented, whereas overexpression of wtPKC-α abrogated, oxidant-induced increases in mitochondrial iHSP70 levels. iHSP70 overexpression 1) maintained mitochondrial levels of phosphorylated PKC-α, 2) improved the recovery of state 3 respiration and ATP content, 3) decreased RPTC death (an effect abrogated by cyclosporine A), and 4) accelerated proliferation after oxidant injury. In contrast, iHSP70 inhibition blocked the recovery of ATP content and exacerbated RPTC death. Inhibition of PKC-α in RPTC overexpressing iHSP70 blocked the protective effects of iHSP70. We conclude that active PKC-α maintains mitochondrial function and decreases cell death after oxidant injury. iHSP70 is recruited to mitochondria in response to PKC-α dephosphorylation and associates with and reactivates inactive PKC-α, which promotes the recovery of mitochondrial function, decreases RPTC death, and improves regeneration.

scholarly journals Native LDL-induced oxidative stress in human proximal tubular cells: multiple players involved

2011 ◽  
Vol 15 (2) ◽  
pp. 375-395 ◽  
Author(s):  
Claudia Piccoli ◽  
Giovanni Quarato ◽  
Annamaria D’Aprile ◽  
Eustacchio Montemurno ◽  
Rosella Scrima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

iPSC differentiating into renal proximal tubular cells are vulnerable to oxidative stress

2020 ◽  
Vol 159 ◽  
pp. S109-S110
Author(s):  
Alexander Meissner ◽  
Cornelia Hirsch ◽  
Gerhard Fritz ◽  
James Adjaye ◽  
Nicole Schupp
Keyword(s):  
Oxidative Stress ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular
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