Oxidant Preconditioning Protects Human Proximal Tubular Cells against Lethal Oxidant Injury via p38 MAPK and Heme Oxygenase-1

2003 ◽  
Vol 23 (5) ◽  
pp. 324-333 ◽  
Author(s):  
H. Thomas Lee ◽  
Hua Xu ◽  
Ayuko Ota-Setlik ◽  
Charles W. Emala
Keyword(s):  
P38 Mapk ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Oxidant Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

scholarly journals Ethyl Pyruvate Directly Attenuates Active Secretion of HMGB1 in Proximal Tubular Cells via Induction of Heme Oxygenase-1

2019 ◽  
Vol 8 (5) ◽  
pp. 629 ◽  
Author(s):  
Min Suk Seo ◽  
Hye Jung Kim ◽  
Hwajin Kim ◽  
Sang Won Park
Keyword(s):  
Heme Oxygenase ◽  
Ethyl Pyruvate ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Tubular Damage ◽  
High Morbidity ◽  
Proximal Tubular Cells ◽  
Active Secretion ◽  
Tubular Cells ◽  
Proximal Tubular

Renal ischemia reperfusion (IR) is a main cause of acute kidney injury leading to high morbidity and mortality during postoperative periods. This study investigated whether ethyl pyruvate (EP) protects the kidney against renal IR injury. Male C57BL/6 mice were treated with vehicle or EP (40 mg/kg) 1 h before ischemia and the plasma creatinine (Cr) levels and tubular damage were evaluated after reperfusion. EP attenuated the IR-induced plasma Cr levels, renal inflammation and apoptotic cell death, but the effect of EP was abolished by pretreating Zinc protoporphyrin (ZnPP), a heme oxygenase (HO)-1 inhibitor. HO-1 is a stress-induced protein and protects the kidney against IR injury. EP increased significantly HO-1 expression in the proximal tubular cells in vivo and HK-2 cells in vitro. Inhibition of PI3K/Akt pathway and knockdown of Nrf2 blocked HO-1 induction by EP. High mobility group box 1 (HMGB1) secretion was assessed as an early mediator of IR injury; plasma HMGB1 were significantly elevated as early as 2 h to 24 h after reperfusion and these were attenuated by EP, but the effect of EP was abolished by ZnPP. EP also reduced HMGB1 secretion stimulated by TNF-α in HK-2 cells, and the inhibition of PI3K/Akt and knockdown of HO-1 blocked the effect of EP. Conclusively, EP inhibits the active secretion of HMGB1 from proximal tubular cells during IR injury by inducing HO-1 via activation of PI3K/Akt and Nrf2 pathway.

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.

Abstract 385: TRPA1 Mediates Angiotensinogen Augmentation in Renal Proximal Tubular Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ryousuke Satou ◽  
Andrea Zsombok ◽  
Andrei V Derbenev
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
P38 Mapk ◽  
Rt Pcr ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Stimulation Of

Overactivity of the intrarenal renin-angiotensin system contributes to the development of hypertension and renal injury. In this process, regulation of angiotensinogen (AGT) in renal proximal tubular cells (RPTC) is a key factor. Oxidative stress stimulates AGT expression accompanied by activation of p38 MAPK in RPTC. Transient receptor potential A1 (TRPA1) is known to be a sensor activated by a variety of noxious stimuli including hydrogen peroxide. Activated TRPA1 induces calcium influx across the plasma membrane leading to activation of AGT-inducible signal transducers. However, the presence and function of TRPA1 in the kidney have not been delineated. Therefore, this study was performed to demonstrate expression of intrarenal TRPA1 and its role in AGT augmentation in RPTC. Expression of TRPA1 in mouse kidney and cultured mouse RPTC were determined by RT-PCR, in situ hybridization, western blot analysis and immunocytochemistry. The RPTC were treated with 100 μM H2O2 for 1 hr with or without 10μM HC030031, a TRPA1 specific antagonist. EGTA was used to the culture medium for depletion of extracellular calcium. Thereafter, AGT expression levels were evaluated by real-time RT-PCR, and TRPA1 expression levels and p38 MAPK activity were determined by western blot analyses. TRPA1 expression was observed in tubules of renal cortex, and the cultured PRTC expressed TRPA1 mRNA and protein. H2O2 increased AGT expression (1.54 ± 0.08, ratio to control) in RPTC. The AGT augmentation was suppressed by HC030031 (1.19 ± 0.05, ratio to control). Calcium depletion also resulted in attenuation of the AGT augmentation induced by H2O2. Although H2O2 induced phosphorylation of p38 MAPK, HC030031 did not inhibit the p38 MAPK activation. TRPA1 expression was increased by H2O2 under the experimental condition (1.90 ± 0.06, ratio to control). These results suggest that TRPA1 is expressed in RPTC, which contributes to H2O2-induced AGT augmentation via calcium-dependent but p38 MAPK-independent pathways. Furthermore, increase in TRPA1 expression by H2O2 likely facilitates the stimulation of AGT expression. Therefore, TRPA1 may play an important role in the progression of oxidative stress-associated renal injury and hypertension via the stimulation of AGT expression in RPTC.

scholarly journals High Glucose Stimulates Angiotensinogen Gene Expression via Reactive Oxygen Species Generation in Rat Kidney Proximal Tubular Cells

Endocrinology ◽  
2002 ◽  
Vol 143 (8) ◽  
pp. 2975-2985 ◽  
Author(s):  
Tusty-Jiuan Hsieh ◽  
Shao-Ling Zhang ◽  
Janos G. Filep ◽  
Shiow-Shih Tang ◽  
Julie R. Ingelfinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
High Glucose ◽  
Ros Generation ◽  
Proximal Tubular Cells ◽  
Mapk Phosphorylation ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells ◽  
Sb 203580

Abstract The present studies investigated whether the effect of high glucose levels on angiotensinogen (ANG) gene expression in kidney proximal tubular cells is mediated via reactive oxygen species (ROS) generation and p38 MAPK activation. Rat immortalized renal proximal tubular cells (IRPTCs) were cultured in monolayer. Cellular ROS generation and p38 MAPK phosphorylation were assessed by lucigenin assay and Western blot analysis, respectively. The levels of immunoreactive rat ANG secreted into the media and cellular ANG mRNA were determined by a specific RIA and RT-PCR, respectively. High glucose (25 mm) evoked ROS generation and p38 MAPK phosphorylation as well as stimulated immunoreactive rat ANG secretion and ANG mRNA expression in IRPTCs. These effects of high glucose were blocked by antioxidants (taurine and tiron), inhibitors of mitochondrial electron transport chain complex I (rotenone) and II (thenoyltrifluoroacetone), an inhibitor of glycolysis-derived pyruvate transport into mitochondria (α-cyano-4-hydroxycinnamic acid), an uncoupler of oxidative phosphorylation (carbonyl cyanide m-chlorophenylhydrazone), a manganese superoxide dismutase mimetic, catalase, and a specific inhibitor of p38 MAPK (SB 203580), but were not affected by an inhibitor of the malate-aspartate shuttle (aminooxyacetate acid). Hydrogen peroxide (≥10−5m) also stimulated p38 MAPK phosphorylation, ANG secretion, and ANG mRNA gene expression, but its stimulatory effect was blocked by catalase and SB 203580. These studies demonstrate that the stimulatory action of high glucose on ANG gene expression in IRPTCs is mediated at least in part via ROS generation and subsequent p38 MAPK activation.

Effects of Sex Hormones on Na+/Glucose Cotransporter of Renal Proximal Tubular Cells following Oxidant Injury

2001 ◽  
Vol 24 (3) ◽  
pp. 159-165 ◽  
Author(s):  
Ho Jae Han ◽  
Soo Hyun Park ◽  
Hyung Joo Park ◽  
Jang Hern Lee ◽  
Byung Cheon Lee ◽  
...  
Keyword(s):  
Sex Hormones ◽  
Oxidant Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Oxidant Preconditioning Protects Human Proximal Tubular Cells Against Lethal Oxidant Injury

2002 ◽  
Vol 96 (Sup 2) ◽  
pp. A409
Author(s):  
H. T. Lee ◽  
Hua Xu ◽  
Ayuko Ota-Setlik ◽  
Charles W. Emala
Keyword(s):  
Oxidant Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular
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