scholarly journals NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage

2017 ◽  
Vol 312 (1) ◽  
pp. C47-C55 ◽  
Author(s):  
Mirandy S. Li ◽  
Sherry E. Adesina ◽  
Carla L. Ellis ◽  
Jennifer L. Gooch ◽  
Robert S. Hoover ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Kidney Damage ◽  
Electrolyte Imbalance ◽  
Tubular Epithelial Cells ◽  
Kidney Hypertrophy

Zn2+ deficiency (ZnD) is comorbid with chronic kidney disease and worsens kidney complications. Oxidative stress is implicated in the detrimental effects of ZnD. However, the sources of oxidative stress continue to be identified. Since NADPH oxidases (Nox) are the primary enzymes that contribute to renal reactive oxygen species generation, this study's objective was to determine the role of these enzymes in ZnD-induced oxidative stress. We hypothesized that ZnD promotes NADPH oxidase upregulation, resulting in oxidative stress and kidney damage. To test this hypothesis, wild-type mice were pair-fed a ZnD or Zn2+-adequate diet. To further investigate the effects of Zn2+ bioavailability on NADPH oxidase regulation, mouse tubular epithelial cells were exposed to the Zn2+ chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn2+ supplementation. We found that ZnD diet-fed mice develop microalbuminuria, electrolyte imbalance, and whole kidney hypertrophy. These markers of kidney damage are accompanied by elevated Nox2 expression and H2O2 levels. In mouse tubular epithelial cells, TPEN-induced ZnD stimulates H2O2 generation. In this in vitro model of ZnD, enhanced H2O2 generation is prevented by NADPH oxidase inhibition with diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation, which are reversed when intracellular Zn2+ levels are restored following Zn2+ supplementation. Finally, Nox2 knockdown by siRNA prevents TPEN-induced H2O2 generation and cellular hypertrophy in vitro. Together, these findings reveal that Nox2 is a Zn2+-regulated enzyme that mediates ZnD-induced oxidative stress and kidney hypertrophy. Understanding the specific mechanisms by which ZnD contributes to kidney damage may have an important impact on the treatment of chronic kidney disease.

Preparation of Gold Nanoparticles and Its Effect on Autophagy and Oxidative Stress in Chronic Kidney Disease Cell Model

2021 ◽  
Vol 21 (2) ◽  
pp. 1266-1271
Author(s):  
Ping Zhao ◽  
Ting Li ◽  
Zhi Li ◽  
Lei Cao ◽  
Youliang Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Gold Nanoparticles ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Membrane Damage ◽  
The Body ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Gold nanoparticles (GNPs) are widely used in life sciences and medicine due to their simple preparation, stable physical and chemical properties, controllable optical properties and no significant toxicity. However, in recent years, studies have found that there are still many uncertain factors in the application of gold nanoparticles in the field of biomedicine, and there are few studies on the main excretion organs and kidneys of the body, especially the toxicological effects under the disease state have not been reported. Obviously, carrying out relevant research is of great significance for accelerating the clinical application of GNPs. Chronic kidney disease (CKD) is a group of chronic progressive diseases that have high prevalence and high mortality and are serious threats to human life and health. Renal tubular injury and interstitial fibrosis are key factors in renal dysfunction in chronic kidney disease. Drug and toxic kidney damage mostly involve renal tubular epithelial cells; hypoxia is the most common pathological condition of cells. In renal lesions, renal tubular epithelial cells often have hypoxia. Based on this, we propose the hypothesis of this study: glomerular filtration membrane damage in kidney disease, GNPs increase in urine, followed by reabsorption of renal tubular epithelial cells, thereby causing damage to the latter; if accompanied by hypoxia, GNPs it will aggravate renal tubular epithelial cell damage and promote tubulointerstitial fibrosis. In order to verify the above hypothesis, this study used a mouse model of adriamycin nephropathy and tubular epithelial cells and macrophages in vitro, and observed the damage of GNPs on renal tubular epithelial cells by various means, and explored related mechanisms. The results show that under normal oxygen conditions, GNPs can induce autophagy after cell entry, which can damage damaged proteins and organelles to maintain cell survival. In the absence of oxygen, nanoparticles entering cells increase and induce excessive autophagy. In the absence of oxygen, GNPs also aggregate in macrophages, which can cause decreased cell proliferation activity and induce activation of macrophage inflammasome, which induces inflammatory response: GNPs-induced secretion of hypoxic macrophages can be promoted.

scholarly journals Therapeutic Effect of Endothelin-Converting Enzyme Inhibitor on Chronic Kidney Disease through the Inhibition of Endoplasmic Reticulum Stress and the NLRP3 Inflammasome

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 398
Author(s):  
Yung-Ho Hsu ◽  
Cai-Mei Zheng ◽  
Chu-Lin Chou ◽  
Yi-Jie Chen ◽  
Yu-Hsuan Lee ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Enzyme Inhibitor ◽  
Inflammasome Activation ◽  
Tubular Epithelial Cells ◽  
Domain 3

Chronic inflammation and oxidative stress significantly contribute to the development and progression of chronic kidney disease (CKD). The NOD-like receptor family pyrin containing domain-3 (NLRP3) inflammasome plays a key role in the inflammatory response. The renal endothelin (ET) system is activated in all cases of CKD. Furthermore, ET-1 promotes renal cellular injury, inflammation, fibrosis and proteinuria. Endothelin-converting enzymes (ECEs) facilitate the final processing step of ET synthesis. However, the roles of ECEs in CKD are not clear. In this study, we investigated the effects of ETs and ECEs on kidney cells. We found that ET-1 and ET-2 expression was significantly upregulated in the renal tissues of CKD patients. ET-1 and ET-2 showed no cytotoxicity on human kidney tubular epithelial cells. However, ET-1 and ET-2 caused endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation in tubular epithelial cells. The ECE inhibitor phosphoramidon induced autophagy. Furthermore, phosphoramidon inhibited ER stress and the NLRP3 inflammasome in tubular epithelial cells. In an adenine diet-induced CKD mouse model, phosphoramidon attenuated the progression of CKD by regulating autophagy, the NLRP3 inflammasome and ER stress. In summary, these findings showed a new strategy to delay CKD progression by inhibiting ECEs through autophagy activation and restraining ER stress and the NLRP3 inflammasome.

scholarly journals Bcl-XL translocation in renal tubular epithelial cells in vitro protects distal cells from oxidative stress

2001 ◽  
Vol 59 (5) ◽  
pp. 1779-1788 ◽  
Author(s):  
Leila Cuttle ◽  
Xiao-Ju Zhang ◽  
Zoltan H. Endre ◽  
Clay Winterford ◽  
Glenda C. Gobé
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

scholarly journals Oxalate-induced activation of PKC-α and -δ regulates NADPH oxidase-mediated oxidative injury in renal tubular epithelial cells

2009 ◽  
Vol 297 (5) ◽  
pp. F1399-F1410 ◽  
Author(s):  
Vijayalakshmi Thamilselvan ◽  
Mani Menon ◽  
Sivagnanam Thamilselvan
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Cell Injury ◽  
Oxidative Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Ldh Release ◽  
Renal Tubular

Oxalate-induced oxidative stress contributes to cell injury and promotes renal deposition of calcium oxalate crystals. However, we do not know how oxalate stimulates reactive oxygen species (ROS) in renal tubular epithelial cells. We investigated the signaling mechanism of oxalate-induced ROS formation in these cells and found that oxalate significantly increased membrane-associated protein kinase C (PKC) activity while at the same time lowering cytosolic PKC activity. Oxalate markedly translocated PKC-α and -δ from the cytosol to the cell membrane. Pretreatment of LLC-PK1cells with specific inhibitors of PKC-α or -δ significantly blocked oxalate-induced generation of superoxide and hydrogen peroxide along with NADPH oxidase activity, LDH release, lipid hydroperoxide formation, and apoptosis. The PKC activator PMA mimicked oxalate's effect on oxidative stress in LLC-PK1cells as well as cytosol-to-membrane translocation of PKC-α and -δ. Silencing of PKC-α expression by PKC-α-specific small interfering RNA significantly attenuated oxalate-induced cell injury by decreasing hydrogen peroxide generation and LDH release. We believe this is the first demonstration that PKC-α- and -δ-dependent activation of NADPH oxidase is one of the mechanisms responsible for oxalate-induced oxidative injury in renal tubular epithelial cells. The study suggests that the therapeutic approach might be considered toward attenuating oxalate-induced PKC signaling-mediated oxidative injury in recurrent stone formers.

scholarly journals PM2.5 exposure induces renal injury via the activation of the autophagic pathway in rat and HK-2 cell

2020 ◽  
Author(s):  
Xiaoliu Huang ◽  
Jue Li
Keyword(s):  
Epithelial Cells ◽  
Renal Injury ◽  
Fine Particulate Matter ◽  
Human Kidney ◽  
Kidney Damage ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Abstract Background Exposure to airborne fine particulate matter (PM2.5) has been declared to be harmful to the human kidney. However, whether activation of the autophagic pathway plays key roles in the nephrotoxicity caused by PM2.5 exposure is still poorly understood. The aim of this study was to explore the mechanism of kidney damage after PM2.5 exposure in vivo and in vitro. Results In the present study, statistically significant alterations in water intake, urine flow rate and mean blood pressure were observed between the PM2.5 group and FA group during the period of PM2.5 exposure. Exposed animals showed severe edema of renal tubular epithelial cells, capillary congestion, reduction of the glomerular urinary space and early pro-fibrotic state. Moreover, significant increases in the levels of early kidney damage markers were observed in the exposed rats and these animals exhibited more apoptosis rate in kidney cells. In addition, PM2.5 exposure resulted in the activation of the autophagic pathway, as evidenced by LC3-I to LC3-II conversion, P62 and beclin-1 activated. All of these effects are in concurrence with the presence of more autophagosomes both in vivo and in vitro after PM2.5 exposure. Conclusions Taken together, our findings indicated that PM2.5-induced renal injury via the activation of the autophagic pathway in renal tubular epithelial cells.

scholarly journals Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hung-Cheng Tsai ◽  
Fu-Pang Chang ◽  
Tzu-Hao Li ◽  
Chih-Wei Liu ◽  
Chia-Chang Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Renal Tubular ◽  
Common Pathogenesis

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.

scholarly journals Underlying Histopathology Determines Response to Oxidative Stress in Cultured Human Primary Proximal Tubular Epithelial Cells

2020 ◽  
Vol 21 (2) ◽  
pp. 560
Author(s):  
Muhammad Ali Khan ◽  
Xiangju Wang ◽  
Kurt T.K. Giuliani ◽  
Purba Nag ◽  
Anca Grivei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Functional Response ◽  
Mitochondrial Function ◽  
Human Kidney ◽  
Tubular Epithelial Cells ◽  
Cortical Tissue ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned. In this study, we investigated the phenotypic and functional response of human primary PTEC to oxidative stress, an established driver of kidney disease. Furthermore, we examined the functional contribution of the underlying histopathology of the cortical tissue used to generate our PTEC. We demonstrated that human primary PTEC from both histologically ‘normal’ and ‘diseased’ cortical tissue responded to H2O2-induced oxidative stress with significantly elevated mitochondrial superoxide levels, DNA damage, and significantly decreased proliferation. The functional response of ‘normal’ PTEC to oxidative stress mirrored the reported pathogenesis of human kidney disease, with significantly attenuated mitochondrial function and increased cell death. In contrast, ‘diseased’ PTEC were functionally resistant to oxidative stress, with maintenance of mitochondrial function and cell viability. This selective survival of ‘diseased’ PTEC under oxidizing conditions is reminiscent of the in vivo persistence of maladaptive PTEC following kidney injury. We are now exploring the impact that these differential PTEC responses have in the therapeutic targeting of oxidative stress pathways.

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