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

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.

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Huaier Cream Protects against Adriamycin-Induced Nephropathy by Restoring Mitochondrial Function via PGC-1αUpregulation

PPAR Research ◽

10.1155/2015/720383 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Ruochen Che ◽

Chunhua Zhu ◽

Guixia Ding ◽

Min Zhao ◽

Mi Bai ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Cell Injury ◽

Therapeutic Drug ◽

Mtdna Copy Number ◽

Glomerular Diseases ◽

Mitochondrial Transcription Factor ◽

Transmission Electron

The mechanism by which Huaier, a Chinese traditional medicine, protects podocytes remains unclear. We designed the present study to examine whether mitochondrial function restored by PGC-1αserves as the major target of Huaier cream in protecting ADR nephropathy. After ADR administration, the podocytes exhibited remarkable cell injury and mitochondrial dysfunction. Additionally, ADR also reduced PGC-1αbothin vivoandin vitro. Following the Huaier treatment, the notable downregulation of PGC-1αand its downstream molecule mitochondrial transcription factor A (TFAM) were almost entirely blocked. Correspondingly, Huaier markedly ameliorated ADR-induced podocyte injury and mitochondrial dysfunction in both rat kidneys and incubated cells as it inhibited the decrease of nephrin and podocin expression, mtDNA copy number, MMP, and ATP content. Transmission electron microscopy result also showed that Huaier protected mitochondria against ADR-induced severe mitophagy and abnormal changes of ultrastructural morphology. In conclusion, Huaier can protect podocytes against ADR-induced cytotoxicity possibly by reversing the dysfunction of mitochondria via PGC-1αoverexpression, which may be a novel therapeutic drug target in glomerular diseases.

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p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction

AJP Renal Physiology ◽

10.1152/ajprenal.00055.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. F798-F808 ◽

Cited By ~ 19

Author(s):

Yanggang Yuan ◽

Aiqing Zhang ◽

Jia Qi ◽

Hui Wang ◽

Xi Liu ◽

...

Keyword(s):

Animal Model ◽

Mitochondrial Dysfunction ◽

Therapeutic Intervention ◽

Mitochondrial Fission ◽

Related Protein ◽

Glomerular Diseases ◽

Podocyte Injury ◽

P53 Expression

Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.

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199 EVIDENCE FOR A NOVEL PERTURBATION IN CLONED FETUSES: MITOCHONDRIAL DNA DEPLETION

Reproduction Fertility and Development ◽

10.1071/rdv19n1ab199 ◽

2007 ◽

Vol 19 (1) ◽

pp. 216

Author(s):

S. Hiendleder ◽

D. Bebbere ◽

S. E. Ulbrich ◽

V. Zakhartchenko ◽

M. Weppert ◽

...

Keyword(s):

Mitochondrial Dna ◽

Real Time ◽

Nuclear Gene ◽

Complement C3 ◽

Mtdna Copy Number ◽

Vitro Fertilization ◽

Mitochondrial Transcription Factor ◽

Mitochondrial Dna Depletion

The reported mtDNA turnover and plasticity of mtDNA copy number in mammalian zygotes and early embryos (McConnel and Petrie 2004 Reprod. Biomed. Online 9, 418–424) have revealed a potential for adverse effects of in vitro embryo techniques on mtDNA and mitochondrial function. We explored the effects of in vitro fertilization (IVF) and somatic cell nuclear transfer cloning (NT) on relative mtDNA amount and phenotype in viable bovine fetuses recovered 80 days after the initiation of embryonic development (Hiendleder et al. 2004 Biol. Reprod. 71, 217–223). We sampled brain, liver, and skeletal muscle to represent all 3 embryonic germ layers, and compared IVF-fetuses (n = 24), NT-fetuses (n = 23), and fetuses generated by in vivo insemination (controls, n = 24). This experimental approach allowed us to distinguish abnormalities specific to cloning from more general consequences of in vitro embryo manipulation. We analyzed relative mtDNA amounts by real-time quantitative PCR (qPCR) and amplified a segment of the mtDNA control region that was normalized against the nuclear gene complement C3. ANOVA (SPSS 13.0) of qPCR data and phenotypic parameters revealed significant effects of fetus group on mtDNA amount in liver (P < 0.05) and muscle (P < 0.01), and on fetus (P < 0.001), heart (P < 0.001), and liver (P < 0.001) weights. The mtDNA amount in all tissues from IVF-fetuses was normal, but mtDNA levels in liver (-23%; P < 0.05) and muscle (-24%; P < 0.01) of NT-fetuses were significantly lower than in controls. Fetuses derived from IVF- or NT-embryos were similar in weight and displayed fetal overgrowth (+19% and +22%; P < 0.001), but only the NT-fetuses were affected by disproportionate hepatomegaly and cardiomegaly with 31% and 49% increases (ANCOVA; P < 0.001) in their respective organ weights. This further partitioned NT-fetuses from IVF-fetuses and identified symptoms that are also encountered in mitochondrial DNA depletion syndromes (MDDS): a phenotypically heterogeneous group of human disorders characterized by loss of mtDNA from various tissues during development and associated respiratory chain dysfunction. The MDDS phenotypes have mainly been classified into a hepatocerebral (MIM 251880) or myopathic (MIM 609560) form, and neonates and infants display a spectrum of abnormalities, including hepatomegaly and cardiomegaly, that are similar or identical to phenotypic abnormalities commonly encountered in cloned mammals. Reduced mtDNA amounts in NT-fetuses could stem from perturbation of mtDNA during the reported turnover period, or be a secondary effect of epigenetic change in nuclear-encoded genes involved in mtDNA replication and stability. Mitochondrial transcription factor A (TFAM) is regulated by CpG methylation in vitro, but our real-time RT-PCR quantification of TFAM transcript in liver and muscle of a subset of NT- and control fetuses failed to detect significant differences (P > 0.10). In conclusion, our observed reduction of mtDNA amount in cloned fetuses provides the molecular basis for a mitochondrial perspective on pathological phenotypes of cloned mammals, and may explain similarities to mitochondrial disease in human.

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Prohibitin‐1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis

Journal of the American Heart Association ◽

10.1161/jaha.120.019877 ◽

2021 ◽

Author(s):

Taylor A. Mattox ◽

Christine Psaltis ◽

Katie Weihbrecht ◽

Jacques Robidoux ◽

Brita Kilburg‐Basnyat ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Blood Protein ◽

Nuclear Factor ◽

In Vivo Models ◽

Endotoxin Challenge ◽

Atp Production ◽

Anti Inflammatory ◽

Prohibitin 1

Background In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown. Methods and Results Using a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT signaling in the heart. Conclusions These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.

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Aldosterone Excess Induced Mitochondria Decrease and Dysfunction via Mineralocorticoid Receptor and Oxidative Stress In Vitro and In Vivo

Biomedicines ◽

10.3390/biomedicines9080946 ◽

2021 ◽

Vol 9 (8) ◽

pp. 946

Author(s):

Cheng-Hsuan Tsai ◽

Chien-Ting Pan ◽

Yi-Yao Chang ◽

Shih-Yuan Peng ◽

Po-Chin Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Mineralocorticoid Receptor ◽

Cardiac Mitochondria ◽

Mice Model ◽

Atp Production ◽

And Oxidative Stress

Aldosterone excess plays a major role in the progression of cardiac dysfunction and remodeling in clinical diseases such as primary aldosteronism and heart failure. However, the effect of aldosterone excess on cardiac mitochondria is unclear. In this study, we investigated the effect of aldosterone excess on cardiac mitochondrial dysfunction and its mechanisms in vitro and in vivo. We used H9c2 cardiomyocytes to investigate the effect and mechanism of aldosterone excess on cardiac mitochondria, and further investigated them in an aldosterone-infused ICR mice model. The results of the cell study showed that aldosterone excess decreased mitochondrial DNA, COX IV and SOD2 protein expressions, and mitochondria ATP production. These effects were abolished or attenuated by treatment with a mineralocorticoid receptor (MR) antagonist and antioxidant. With regard to the signal transduction pathway, aldosterone suppressed cardiac mitochondria through an MR/MAPK/p38/reactive oxygen species pathway. In the mouse model, aldosterone infusion decreased the amount of cardiac mitochondrial DNA and COX IV protein, and the effects were also attenuated by treatment with an MR antagonist and antioxidant. In conclusion, aldosterone excess induced a decrease in mitochondria and mitochondrial dysfunction via MRs and oxidative stress in vitro and in vivo.

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SIRT1 Alleviates Aldosterone-Induced Podocyte Injury by Suppressing Mitochondrial Dysfunction and NLRP3 Inflammasome Activation

Kidney Diseases ◽

10.1159/000513884 ◽

2021 ◽

pp. 1-13

Author(s):

Mingzhu Jiang ◽

Min Zhao ◽

Mi Bai ◽

Juan Lei ◽

Yanggang Yuan ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Knockout Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Glomerular Injury ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation

Background: Podocyte injury contributes to progressive glomerulosclerosis. Previously, we demonstrated the important role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mediating the podocyte injury induced by aldosterone. Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+-dependent deacetylase that is associated with the regulation of cellular inflammation. However, whether the activation of the NLRP3 inflammasome in podocytes is regulated by SIRT1, and the mechanism involved, remains unknown. Methods: In this study, we detected SIRT1 expression in patients with podocyte disease and performed an aldosterone infusion model in podocyte-specific Sirt1 knockout mice. In cultured podocytes, we used plasmids to overexpress SIRT1 and treated the podocyte with aldosterone. Results: SIRT1 was significantly decreased in the glomeruli of patients with podocyte disease. Sirt1-deficient mice showed significant urinary albumin excretion after aldosterone infusion, and the severity of the glomerular injury was significantly greater in podocyte-specific Sirt1 knockout mice than in the wild-type mice. Moreover, podocyte conditional Sirt1 knockout aggravated NLRP3 inflammasome activation and mitochondrial dysfunction (MtD). In vitro, overexpression of SIRT1 inhibited NLRP3 activation, protected against MtD and podocyte injury. Conclusion: Taken together, these findings revealed a novel regulatory mechanism of the NLRP3 inflammasome by SIRT1 by promoting mitochondrial function, which provides some potential targets for the treatment of glomerular diseases.

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mPGES-1-derived PGE2 contributes to adriamycin-induced podocyte injury

AJP Renal Physiology ◽

10.1152/ajprenal.00499.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. F492-F498 ◽

Cited By ~ 6

Author(s):

Jing Yu ◽

Wei Gong ◽

Yimei Wu ◽

Shuzhen Li ◽

Yiyun Cui ◽

...

Keyword(s):

Underlying Mechanism ◽

Pathological Feature ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Phenotypic Alteration ◽

Tnf Α ◽

Progression Of Kidney Disease

Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL-1β and TNF-α were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF-α, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response.

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TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

Cellular Physiology and Biochemistry ◽

10.1159/000430174 ◽

2015 ◽

Vol 36 (5) ◽

pp. 2072-2082 ◽

Cited By ~ 21

Author(s):

Peng Zhang ◽

Yong Lu ◽

Dong Yu ◽

Dadong Zhang ◽

Wei Hu

Keyword(s):

Cell Death ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Ros Generation ◽

Complex Activity ◽

Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

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Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro

AJP Renal Physiology ◽

10.1152/ajprenal.00608.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. F1372-F1380 ◽

Cited By ~ 28

Author(s):

Gabriela Casalena ◽

Stefanie Krick ◽

Ilse Daehn ◽

Liping Yu ◽

Wenjun Ju ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Oxidative Dna Damage ◽

Ros Generation ◽

Glomerular Injury ◽

Inner Mitochondrial Membrane ◽

Glomerular Diseases ◽

Mtdna Mutations ◽

Mitochondrial Ros

Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17+/+ wild-type (WT) and Mpv17−/− knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.

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