scholarly journals Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease

2015 ◽  
Vol 128 (9) ◽  
pp. 527-535 ◽  
Author(s):  
Andrew S. Brem ◽  
Rujun Gong
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mesangial Cells ◽  
Glycogen Synthase ◽  
Collecting Duct ◽  
Electrolyte Transport ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Sclerosis ◽  
Early Event ◽  
Glomerular Diseases

Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where ‘classical’ mineralocorticoid receptors (MRs) involved with electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, ‘non-classical’ MRs have been described in kidney cells not associated with electrolyte transport, including mesangial cells and podocytes within the glomerulus. Activation of MRs in these cells appears to lead to glomerular sclerosis. Mechanistically, aldosterone induces excess production of reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of NADPH oxidase. In mesangial cells, aldosterone also has pro-apoptotic, mitogenic and pro-fibrogenic effects, all of which potentially promote active remodelling and expansion of the mesangium. Although mitochondrial dysfunction seems to mediate the aldosterone-induced mesangial apoptosis, the ROS dependent epithelial growth factor receptor (EGFR) transactivation is probably responsible for aldosterone-induced mesangial mitosis and proliferation. In podocytes, mitochondrial dysfunction elicited by oxidative stress is an early event associated with aldosterone-induced podocyte injury. Both the p38 MAPK (p38 mitogen-activated protein kinase) signalling and the redox-sensitive glycogen synthase kinase (GSK)3β pathways are centrally implicated in aldosterone-induced podocyte death. Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically, proteinuria significantly decreases when aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that mineralocorticoids are important players in glomerular pathology.

scholarly journals Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and inIn VivoNeurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

2015 ◽  
Vol 35 (11) ◽  
pp. 1992-2006 ◽  
Author(s):  
Sarah Iqbal ◽  
Shannon Howard ◽  
Philip V. LoGrasso
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Glycogen Synthase ◽  
Reactive Oxygen Species Generation ◽  
Mitogen Activated Protein Kinase ◽  
Endogenous Expression ◽  
6 Hydroxydopamine

Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpressionin vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell deathin vitroandin vivoby inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3β (GSK3β) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3β pathways.

scholarly journals Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress

2016 ◽  
Vol 311 (6) ◽  
pp. F1308-F1317 ◽  
Author(s):  
Leopoldo Raij ◽  
Runxia Tian ◽  
Jenny S. Wong ◽  
John C. He ◽  
Kirk N. Campbell
Keyword(s):  
Oxidative Stress ◽  
Glomerular Filtration ◽  
Biologically Active ◽  
Current Evidence ◽  
Glomerular Sclerosis ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Focal Segmental Glomerular Sclerosis

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap −/− model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2−) that promotes endothelin-1 synthesis. Plg via O2− also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a “second hit” in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.

Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells

2002 ◽  
Vol 282 (6) ◽  
pp. F981-F990 ◽  
Author(s):  
Luis Michea ◽  
Christian Combs ◽  
Peter Andrews ◽  
Natalia Dmitrieva ◽  
Maurice B. Burg
Keyword(s):  
Mitochondrial Dysfunction ◽  
Collecting Duct ◽  
Early Event ◽  
Mitochondrial Morphology ◽  
Cytochrome C Release ◽  
Activity Increase ◽  
Transmission Electron ◽  
Mitochondrial Membrane Depolarization ◽  
Medullary Collecting Duct ◽  
Induced Apoptosis

Raising osmolality to 700 mosmol/kgH2O by the addition of NaCl rapidly kills most murine inner renal medullary collecting duct cells (mIMCD3), but they survive at 500 mosmol/kgH2O. At 300 and 500 mosmol/kgH2O, NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 s to 30 min at 700 mosmol/kgH2O, the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased tetramethylrhodamine methyl ester perchlorate (TMRM) fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within 1–6 h. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning 1 h after osmolality is raised to 700, but not to 500, mosmol/kgH2O. General caspase activity and caspase-9 activity increase only after 6 h at 700 mosmol/kgH2O. The mitochondrial Bcl-2/Bax ratio decreases within 1–3 h, but no cytochrome c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kgH2O does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis.

scholarly journals The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2

1998 ◽  
Vol 336 (1) ◽  
pp. 241-246 ◽  
Author(s):  
Morag SHAW ◽  
Philip COHEN ◽  
Dario R. ALESSI
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Protein Kinase ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Osmotic Shock ◽  
Mitogen Activated Protein Kinase ◽  
Protein Synthesis Inhibitor ◽  
Mitogen Activated Protein ◽  
Sb 203580

Protein kinase B (PKB) isoforms became activated [and glycogen synthase kinase-3 (GSK3) became inhibited] when mouse Swiss 3T3 fibroblasts were exposed to oxidative stress (H2O2) or heat shock, but not when they were exposed to osmotic shock (0.5 M sorbitol or 0.7 M NaCl), chemical stress (sodium arsenite), the protein-synthesis inhibitor anisomycin, or UV radiation. In contrast, all seven stimuli activated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2). The activation of MAPKAP-K2 was suppressed by the drug SB 203580, but not by inhibitors of phosphoinositide (phosphatidylinositide, PI) 3-kinase. In contrast, the activation of PKB isoforms and the inhibition of GSK3 by oxidative stress or heat shock were prevented by inhibitors of PI 3-kinase, but not by SB 203580. Thus the activation of PKB by oxidative stress or heat shock is mediated by PI 3-kinase and not by MAPKAP-K2. PKBα and PKBγ were also activated by heat shock and oxidative stress in human embryonic kidney 293 cells and PKBγ was activated by heat shock in NIH 3T3 cells; in each case activation was suppressed by inhibitors of PI 3-kinase. The activation of PKB isoforms by H2O2 may underlie some of the insulin-mimetic effects of this compound.

scholarly journals Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 293
Author(s):  
Axel Römer ◽  
Thomas Linn ◽  
Sebastian F. Petry
Keyword(s):  
Oxidative Stress ◽  
Fatty Acids ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Cell Function ◽  
Radical Scavenging ◽  
Mitogen Activated Protein Kinase ◽  
Β Cells ◽  
Β Cell ◽  
Positive Effects

Lipotoxicity is a major contributor to type 2 diabetes mainly promoting mitochondrial dysfunction. Lipotoxic stress is mediated by elevated levels of free fatty acids through various mechanisms and pathways. Impaired peroxisome proliferator-activated receptor (PPAR) signaling, enhanced oxidative stress levels, and uncoupling of the respiratory chain result in ATP deficiency, while β-cell viability can be severely impaired by lipotoxic modulation of PI3K/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways. However, fatty acids are physiologically required for an unimpaired β-cell function. Thus, preparation, concentration, and treatment duration determine whether the outcome is beneficial or detrimental when fatty acids are employed in experimental setups. Further, ageing is a crucial contributor to β-cell decay. Cellular senescence is connected to loss of function in β-cells and can further be promoted by lipotoxicity. The potential benefit of nutrients has been broadly investigated, and particularly polyphenols were shown to be protective against both lipotoxicity and cellular senescence, maintaining the physiology of β-cells. Positive effects on blood glucose regulation, mitigation of oxidative stress by radical scavenging properties or regulation of antioxidative enzymes, and modulation of apoptotic factors were reported. This review summarizes the significance of lipotoxicity and cellular senescence for mitochondrial dysfunction in the pancreatic β-cell and outlines potential beneficial effects of plant-based nutrients by the example of polyphenols.

scholarly journals Glyoxal-Lysine Dimer, an Advanced Glycation End Product, Induces Oxidative Damage and Inflammatory Response by Interacting with RAGE

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1486
Author(s):  
Hee-Weon Lee ◽  
Min Ji Gu ◽  
Yoonsook Kim ◽  
Jee-Young Lee ◽  
Seungju Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Oxidative Damage ◽  
Inflammatory Responses ◽  
Mesangial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Advanced Glycation ◽  
Advanced Glycation End Product ◽  
Mitogen Activated Protein

The glyoxal-lysine dimer (GOLD), which is a glyoxal (GO)-derived advanced glycation end product (AGE), is produced by the glycation reaction. In this study, we evaluated the effect of GOLD on the oxidative damage and inflammatory response in SV40 MES 13 mesangial cells. GOLD significantly increased the linkage with the V-type immunoglobulin domain of RAGE, a specific receptor of AGE. We found that GOLD treatment increased RAGE expression and reactive oxygen species (ROS) production in mesangial cells. GOLD remarkably regulated the protein and mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and glyoxalase 1 (GLO1). In addition, mitochondrial deterioration and inflammation occurred via GOLD-induced oxidative stress in mesangial cells. GOLD regulated the mitogen-activated protein kinase (MAPK) and the release of proinflammatory cytokines associated with the inflammatory mechanism of mesangial cells. Furthermore, oxidative stress and inflammatory responses triggered by GOLD were suppressed through RAGE inhibition using RAGE siRNA. These results demonstrate that the interaction of GOLD and RAGE plays an important role in the function of mesangial cells.

scholarly journals Fucoxanthin, a Marine Carotenoid, Attenuates β-Amyloid Oligomer-Induced Neurotoxicity Possibly via Regulating the PI3K/Akt and the ERK Pathways in SH-SY5Y Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jiajia Lin ◽  
Jie Yu ◽  
Jiaying Zhao ◽  
Ke Zhang ◽  
Jiachen Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Neuronal Loss ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Neuroprotective Effects ◽  
Amyloid A ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of β-amyloid (Aβ) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented Aβ oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells. Aβ oligomers inhibited the prosurvival phosphoinositide 3-kinase (PI3K)/Akt cascade and activated the proapoptotic extracellular signal-regulated kinase (ERK) pathway. Moreover, inhibitors of glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase (MEK) synergistically prevented Aβ oligomer-induced neuronal death, suggesting that the PI3K/Akt and ERK pathways might be involved in Aβ oligomer-induced neurotoxicity. Pretreatment with fucoxanthin significantly prevented Aβ oligomer-induced alteration of the PI3K/Akt and ERK pathways. Furthermore, LY294002 and wortmannin, two PI3K inhibitors, abolished the neuroprotective effects of fucoxanthin against Aβ oligomer-induced neurotoxicity. These results suggested that fucoxanthin might prevent Aβ oligomer-induced neuronal loss and oxidative stress via the activation of the PI3K/Akt cascade as well as inhibition of the ERK pathway, indicating that further studies of fucoxanthin and related compounds might lead to a useful treatment of AD.

Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury

2013 ◽  
Vol 305 (4) ◽  
pp. F520-F531 ◽  
Author(s):  
Min Su ◽  
Asish-Roopchand Dhoopun ◽  
Yanggang Yuan ◽  
Songming Huang ◽  
Chunhua Zhu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Event ◽  
Mtdna Copy Number ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Atp Production ◽  
Podocyte Damage ◽  
Mitochondrial Transcription Factor

We previously showed that mitochondrial dysfunction (MtD) is involved in an aldosterone (Aldo)-induced podocyte injury. Here, the potential role of MtD in the initiation of podocyte damage was investigated. We detected the dynamic changes of urinary protein, urinary F2-isoprostane and renal malondialdehyde levels, kidney ultrastructure morphology, mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (ΔΨm), and nephrin and podocin expressions in Aldo-infused mice. Aldo infusion first induced renal oxidative stress, as evidenced by increased levels of urinary F2-isoprostane and renal malondialdehyde, and MtD, as demonstrated by reduced mtDNA, ΔΨm, and ATP production. Later, at 5 days after Aldo infusion, proteinuria and podocyte injury began to appear. In cultured podocytes, Aldo or hydrogen peroxide (H2O2) induced MtD after 2–8 h of treatment, whereas the podocyte damage, as shown by decreased nephrin and podocin expressions, occurred later after 12 h of treatment. Thus Aldo treatment both in vitro and in vivo indicated that MtD occurred before podocyte damage. Additionally, MtDNA depletion by ethidium bromide or mitochondrial transcription factor A (TFAM) RNAi induced MtD, further promoting podocyte damage. TFAM expression was found to be reduced in Aldo-infused mice and Aldo-treated podocytes. Adenoviral vector-mediated overexpression of TFAM prevented Aldo-induced MtD and protected against podocyte injury. Together, these findings support MtD as an early event in podocyte injury, and manipulation of TFAM may be a novel strategy for treatment of glomerular diseases such as podocytopathy.

scholarly journals The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Chao Yu ◽  
Jian-Hui Xiao
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Direct Interaction ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Sequestosome 1 ◽  
Molecular Damage

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

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