scholarly journals Podocyte bioenergetics in the development of diabetic nephropathy: the role of mitochondria

Endocrinology ◽  
2021 ◽  
Author(s):  
Irena Audzeyenka ◽  
Agnieszka Bierżyńska ◽  
Abigail C Lay
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Signalling Pathways ◽  
Cell Type ◽  
Cellular Functions ◽  
Podocyte Injury ◽  
Underlying Pathogenesis ◽  
Novel Therapeutic

Abstract Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

scholarly journals Mitochondrial Function, Biology, and Role in Disease

2016 ◽  
Vol 118 (12) ◽  
pp. 1960-1991 ◽  
Author(s):  
Elizabeth Murphy ◽  
Hossein Ardehali ◽  
Robert S. Balaban ◽  
Fabio DiLisa ◽  
Gerald W. Dorn ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Mitochondrial Function ◽  
The United States ◽  
Therapeutic Interventions ◽  
Therapeutic Approaches ◽  
Mitochondrial Defects ◽  
Exciting Time ◽  
Insight Into ◽  
Novel Therapeutic

Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.

Wnt signaling and podocyte dysfunction in diabetic nephropathy

2017 ◽  
Vol 65 (8) ◽  
pp. 1093-1101 ◽  
Author(s):  
Madhura Bose ◽  
Sadia Almas ◽  
Sharma Prabhakar
Keyword(s):  
Diabetes Mellitus ◽  
Renal Failure ◽  
Diabetic Nephropathy ◽  
Wnt Signaling ◽  
Therapeutic Strategies ◽  
Podocyte Injury ◽  
Functional Changes ◽  
Terminal Renal Failure ◽  
Cardiovascular Morbidity And Mortality

Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to cardiovascular morbidity and mortality. Despites continuous advances, the pathogenesis of diabetic nephropathy remains poorly understood. Recent studies have underscored the significance of structural and functional changes in podocytes in the development and progression of diabetic nephropathy. The role of podocytes in health and diabetic nephropathy and abnormalities including podocyte hypertrophy, effacement, and apoptosis, and a detailed discussion on the role played by the Wnt-β-catenin signaling pathway in podocyte injury and dysfunction are the focus of this review. In addition, the role played by Wnt signaling in mediating the effects of known therapeutic strategies for diabetic nephropathy is also discussed.

scholarly journals The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanfen Tang ◽  
Ming Yang ◽  
Yinghong Liu ◽  
Hong Liu ◽  
Lin Sun ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
Renal Damage ◽  
Essential Role ◽  
Inflammatory Factors ◽  
Tubular Injury ◽  
Inflammatory Damage ◽  
First Time ◽  
Novel Therapeutic

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.

scholarly journals Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

2019 ◽  
Author(s):  
Rajkishor Nishad ◽  
Dhanunjay Mukhi ◽  
Ashish Kumar Singh ◽  
Kumaraswami Chintala ◽  
Prasad Tammineni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Hormone ◽  
Cell Death ◽  
Diabetic Nephropathy ◽  
Notch Signaling ◽  
Mitotic Catastrophe ◽  
Podocyte Injury ◽  
Tgf Β1 ◽  
Notch Activation

AbstractPodocytes are integral members of the filtration barrier in the kidney and are crucial for glomerular permselectivity. Podocytes are highly differentiated and vulnerable to an array of noxious stimuli during various clinical conditions whereas podocyte loss plays a key role in progressive glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetics. Previous studies have shown that podocytes express GH receptors (GHR), and induce Notch signaling when exposed to GH. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. In the present study, we demonstrate that GH induces cognate TGF-β1 signaling and provokes cell cycle re-entry of otherwise quiescent podocytes. Though, differentiated podocytes re-enter the cell cycle in response to GH and TGF-β1 unable to accomplish cytokinesis, despite nuclear division. Owing to this aberrant cell-cycle events significant amount of GH or TGF-β1 treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of GHR, TGFBR1, or Notch signaling prevented cell cycle re-entry and protects podocyte from cell death. Furthermore, inhibition of Notch activation prevents GH-dependent podocyte injury and proteinuria. Kidney biopsy sections from patients with diabetic nephropathy show activation of Notch signaling and bi-nucleated podocytes. All these data confirm that excess GH induces Notch1 signaling via TGF-β1 and contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signaling in the podocytopathy and the potential application of inhibitors of TGF-β1 or Notch inhibitors as a therapeutic agent for diabetic nephropathy.Significance StatementElevated circulating levels of growth hormone (GH) associated with glomerular hypertrophy and proteinuria. Whereas decreased GH action protected against proteinuria. Podocytes are highly differentiated cells that play a vital role in glomerular filtration and curb protein loss. The direct role of GH in podocytes is the focus of our study. We found that GH induces TGF-β1 and both provoke cell cycle re-entry of podocytes in Notch1 dependent manner. Notch activation enables the podocytes to accomplish karyokinesis, but not cytokinesis owing to which podocytes remain binucleated. Binucleated podocytes that were observed during GH/TGF-β1 treatment are susceptible to cell death. Our study highlighted the fact that enforcing the differentiated podocytes to re-enter the cell cycle results in mitotic catastrophe and permanent loss.

The Role of Mitochondria in Systemic Lupus Erythematosus: A Glimpse of Various Pathogenetic Mechanisms

2020 ◽  
Vol 27 (20) ◽  
pp. 3346-3361 ◽  
Author(s):  
Shi-Kun Yang ◽  
Hao-Ran Zhang ◽  
Shu-Peng Shi ◽  
Ying-Qiu Zhu ◽  
Na Song ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mitochondrial Dysfunction ◽  
Lupus Erythematosus ◽  
Mitochondrial Dynamics ◽  
Therapeutic Targets ◽  
High Recurrence Rate ◽  
Systemic Lupus ◽  
Inflammatory Reactions ◽  
Novel Therapeutic

Background: Systemic Lupus Erythematosus (SLE) is a polysystem autoimmune disease that adversely affects human health. Various organs can be affected, including the kidney or brain. Traditional treatment methods for SLE primarily rely on glucocorticoids and immunosuppressors. Unfortunately, these therapeutic agents cannot prevent a high recurrence rate after SLE remission. Therefore, novel therapeutic targets are urgently required. Methods: A systematic search of the published literature regarding the abnormal structure and function of mitochondria in SLE and therapies targeting mitochondria was performed in several databases. Results: Accumulating evidence indicates that mitochondrial dysfunction plays important roles in the pathogenesis of SLE, including influencing mitochondrial DNA damage, mitochondrial dynamics change, abnormal mitochondrial biogenesis and energy metabolism, mitophagy, oxidative stress, inflammatory reactions, apoptosis and NETosis. Further investigation of mitochondrial pathophysiological roles will result in further clarification of SLE. Specific lupus-induced organ damage also exhibits characteristic mitochondrial changes. Conclusion: This review aimed to summarize the current research on the role of mitochondrial dysfunction in SLE, which will necessarily provide potential novel therapeutic targets for SLE.

scholarly journals The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

2019 ◽  
Vol 316 (2) ◽  
pp. E293-E304 ◽  
Author(s):  
Simon T. Bond ◽  
Sarah C. Moody ◽  
Yingying Liu ◽  
Mete Civelek ◽  
Claudio J. Villanueva ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mouse Strains ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Genes ◽  
And Function

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

scholarly journals Regulation of TGF-β signalling by protein phosphatases

2010 ◽  
Vol 430 (2) ◽  
pp. 191-198 ◽  
Author(s):  
Ting Liu ◽  
Xin-Hua Feng
Keyword(s):  
Growth Factor ◽  
Essential Role ◽  
Transforming Growth Factor ◽  
Protein Phosphatases ◽  
Transforming Growth Factor Β ◽  
Signalling Pathways ◽  
Signal Transducer ◽  
Cellular Functions ◽  
Phosphorylation Cascade

Tight regulation of TGF-β (transforming growth factor-β) superfamily signalling is important for normal cellular functions and tissue homoeostasis. Since TGF-β superfamily signalling pathways are activated by a short phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor-activated Smads), reversible phosphorylation serves as a critical step to assure proper TGF-β signalling. The present article will review the current progress on the understanding of dynamic phosphorylation in TGF-β signalling and the essential role of protein phosphatases in this process.

scholarly journals Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

2021 ◽  
Vol 11 ◽  
Author(s):  
Sumana Shrestha ◽  
Alaide Morcavallo ◽  
Chiara Gorrini ◽  
Louis Chesler
Keyword(s):  
Transcription Factor ◽  
Brain Tumour ◽  
Therapeutic Target ◽  
Tumour Growth ◽  
Biological Role ◽  
Signalling Pathways ◽  
Paediatric Brain Tumour ◽  
Worse Prognosis ◽  
Novel Therapeutic

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

Study of long non-coding RNA and mitochondrial dysfunction in diabetic rats

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Haytham K Kamal ◽  
Amr S Moustafa ◽  
Wael M Elayat ◽  
Noha N Lasheen ◽  
Azza H AbouGhalia
Keyword(s):  
Lipid Profile ◽  
Histological Examination ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Diabetic Rats ◽  
Diabetic Group ◽  
Diabetic Heart ◽  
Albino Rats ◽  
Diabetic Kidney

Abstract Diabetes mellitus (DM) is a worldwide health problem. Many factors participate in the pathogenesis of DM, including genetic, autoimmune, metabolic, dietary and environmental factors. Intact mitochondrial function is essential for prompt cellular metabolism and energy balance. Malfunctioning mitochondria lead to disturbed glucose metabolism and therefore evolving of DM. Epigenetics plays a role in the control of geneencoded proteins of mitochondrial function and dynamics. One of the primary epigenetic effectors is a family of long non-coding RNAs. The role of lncRNA, H19 in the regulation of mitochondrial dynamics has been recently investigated. The Aim of the work This study aims to evaluate the possible functional role of lncRNA, H19 and its relation to mitofusin-2 (MFN2) expression in diabetic rats. Subjects and methods This study was performed on adult male albino rats divided into diabetic and control groups. Induction of type 1 DM was conducted through single intraperitoneal injection of streptozotocin. Serum measurement of glucose, lipid profile, urea, creatinine, and creatine kinase were performed. Blood pressure measurement, ECG recording, and echocardiography were also performed. Histological examination of cardiac and renal tissues was also performed. In addition, quantitative expression of cardiac and renal tissue MFN2 and lncRNA H19 was determined using qPCR. Results Serum CK-MB and lipid profile levels were markedly elevated in diabetic group compared to controls. Also, kidney functions (serum creatinine, creatinine clearance and albumin creatinine ratio) were markedly elevated in diabetic group compared to controls. Histological examination revealed necrotic changes and intercellular micro hemorrhages in both cardiac and renal tissues of diabetic rats. Expression level of MFN2 gene was lower in diabetic heart and significantly lower in diabetic kidney, as compared to control. Expression of lncRNA H19 was higher in diabetic heart and diabetic kidney as compared to control but without statistical significance. Conclusion In diabetic rats, hyperglycemia had inverse relationship with mitofusin expression and direct proportional relationship with H19 expression. We concluded that hyperglycemia has effect on mitochondrial dynamics suppressing fusion in favor of fission and mitophagy, while H19 expression serve to counterpart the effect of hyperglycemia. In the future, MFN and H19 could serve as potential therapeutic target to reverse effects of hyperglycemia and its complications in DM.

scholarly journals Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI

2017 ◽  
Vol 29 (1) ◽  
pp. 194-206 ◽  
Author(s):  
Heather M. Perry ◽  
Liping Huang ◽  
Rebecca J. Wilson ◽  
Amandeep Bajwa ◽  
Hiromi Sesaki ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Related Protein

The proximal tubule epithelium relies on mitochondrial function for energy, rendering the kidney highly susceptible to ischemic AKI. Dynamin-related protein 1 (DRP1), a mediator of mitochondrial fission, regulates mitochondrial function; however, the cell-specific and temporal role of DRP1 in AKI in vivo is unknown. Using genetic murine models, we found that proximal tubule–specific deletion of Drp1 prevented the renal ischemia-reperfusion–induced kidney injury, inflammation, and programmed cell death observed in wild-type mice and promoted epithelial recovery, which associated with activation of the renoprotective β-hydroxybutyrate signaling pathway. Loss of DRP1 preserved mitochondrial structure and reduced oxidative stress in injured kidneys. Lastly, proximal tubule deletion of DRP1 after ischemia-reperfusion injury attenuated progressive kidney injury and fibrosis. These results implicate DRP1 and mitochondrial dynamics as an important mediator of AKI and progression to fibrosis and suggest that DRP1 may serve as a therapeutic target for AKI.

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