Mitochondrial dysfunction and the AKI-to-CKD transition

2020 ◽  
Vol 319 (6) ◽  
pp. F1105-F1116
Author(s):  
Mingzhu Jiang ◽  
Mi Bai ◽  
Juan Lei ◽  
Yifan Xie ◽  
Shuang Xu ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Mitochondrial Homeostasis ◽  
Cycle Arrest ◽  
Persistent Inflammation ◽  
Acute Injuries ◽  
Nephron Loss ◽  
Effective Therapeutic Strategy

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice

2018 ◽  
Vol 24 (26) ◽  
pp. 3072-3083 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Angham Ibrahim ◽  
MD Mizanur Rahman ◽  
Ali H. Eid ◽  
Shankar Munusamy
Keyword(s):  
Therapeutic Strategy ◽  
Kidney Diseases ◽  
Vascular Dysfunction ◽  
Dicarbonyl Compound ◽  
Renal Complications ◽  
Lysine Residues ◽  
Patients With Diabetes ◽  
Prevalence Of Diabetes Mellitus

Background: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound – is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. Conclusion: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

scholarly journals The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 347 ◽  
Author(s):  
Miguel Fontecha-Barriuso ◽  
Diego Martin-Sanchez ◽  
Julio Manuel Martinez-Moreno ◽  
Maria Monsalve ◽  
Adrian Mario Ramos ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pde Inhibitors ◽  
Its Gene ◽  
Attractive Therapeutic Target ◽  
Amp Activated Protein Kinase

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

scholarly journals The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lihong Mao ◽  
Tianming Zhao ◽  
Yan Song ◽  
Lin Lin ◽  
Xiaofei Fan ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Therapeutic Strategy ◽  
Kidney Injury ◽  
Hepatic Disease ◽  
Therapeutic Concept ◽  
Regulated Cell Death ◽  
Dependent Form ◽  
Molecular Machinery

Abstract Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

scholarly journals GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal lipid and energy metabolism homeostasis: revealed by metabolomics

2017 ◽  
Author(s):  
Chengshi Wang ◽  
Ling Li ◽  
Shuyun Liu ◽  
Guangneng Liao ◽  
Younan Chen ◽  
...  
Keyword(s):  
Renal Function ◽  
Energy Metabolism ◽  
High Fat Diet ◽  
Receptor Agonist ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Direct Role ◽  
Chronic Kidney Injury ◽  
Metabolomic Data

AbstractIncreasing evidence indicate that obesity is highly associated with chronic kidney disease (CKD).GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited metabolic disorders including elevated body weight, hyperlipidemia and impaired glucose tolerance, and remarkable renal injuries including declined renal function and inflammatory/fibrotic changes, whereas Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and NAD+ in the kidney of HDF rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HDF rats. This study suggested that Lira alleviated HFD-induced kidney injury via directly restoring renal lipid and energy metabolism, and GLP-1 receptor agonist is a promising therapy for obesity-associated CKD.

scholarly journals Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases

2021 ◽  
Vol 11 (8) ◽  
pp. 820
Author(s):  
Mengyuan Ge ◽  
Sandra Merscher ◽  
Alessia Fornoni
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Recent Progress ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Glomerular Diseases ◽  
Intracellular Lipids ◽  
Lipid Modifying Agents ◽  
Made In

Although dyslipidemia is associated with chronic kidney disease (CKD), it is more common in nephrotic syndrome (NS), and guidelines for the management of hyperlipidemia in NS are largely opinion-based. In addition to the role of circulating lipids, an increasing number of studies suggest that intrarenal lipids contribute to the progression of glomerular diseases, indicating that proteinuric kidney diseases may be a form of “fatty kidney disease” and that reducing intracellular lipids could represent a new therapeutic approach to slow the progression of CKD. In this review, we summarize recent progress made in the utilization of lipid-modifying agents to lower renal parenchymal lipid accumulation and to prevent or reduce kidney injury. The agents mentioned in this review are categorized according to their specific targets, but they may also regulate other lipid-relevant pathways.

scholarly journals IL-20 in Acute Kidney Injury: Role in Pathogenesis and Potential as a Therapeutic Target

2020 ◽  
Vol 21 (3) ◽  
pp. 1009
Author(s):  
Tian-Yu Lin ◽  
Yu-Hsiang Hsu
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Risk Factor ◽  
Renal Fibrosis ◽  
Inflammatory Mediator ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Pro Inflammatory Cytokines

Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and inflammation are hallmarks in kidney diseases. Various cytokines contribute to the progression of renal diseases; thus, many drugs that specifically block cytokine function are designed for disease amelioration. Numerous studies showed IL-20 functions as a pro-inflammatory mediator to regulate cytokine expression in several inflammation-mediated diseases. In this review, we will outline the effects of pro-inflammatory cytokines in the pathogenesis of AKI and CKD. We also discuss the role of IL-20 in kidney diseases and provide a potential therapeutic approach of IL-20 blockade for treating renal diseases.

scholarly journals Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

2020 ◽  
Vol 11 ◽  
Author(s):  
Rossana Franzin ◽  
Alessandra Stasi ◽  
Marco Fiorentino ◽  
Giovanni Stallone ◽  
Vincenzo Cantaluppi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Complement System ◽  
Kidney Diseases ◽  
Critical Role ◽  
Graft Function ◽  
Kidney Injury ◽  
Increased Risk ◽  
Wide Range ◽  
Renal Aging

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

Environmental Toxins and the Kidney

2019 ◽  
pp. 147-154
Author(s):  
Joshua D. King ◽  
Bernard G. Jaar
Keyword(s):  
Heavy Metals ◽  
Kidney Disease ◽  
Kidney Diseases ◽  
Food Additives ◽  
Kidney Injury ◽  
Toxic Agent ◽  
Toxic Agents ◽  
Relationship Of ◽  
The Relationship

While many compounds are known to be environmental and occupational nephrotoxins, it is often difficult to define the exact contribution of individual toxins to the development of kidney disease. This chapter discusses the relationship of environmental and occupational toxins to kidney diseases, explores the pathogenesis of nephrotoxicity of specific agents, stresses the importance of removal from the toxic agent(s), and describes considerations relevant to medical treatment of selected toxic exposures causative of kidney disease. A number of individual nephrotoxins such as heavy metals, silica compounds, herbal medications, and food additives are discussed in more detail, as is the epidemiology of chronic kidney disease and acute kidney injury due to environmental and occupational toxins. Options for treatment and controversies pertaining to the therapy of toxic agents causative of kidney disease are explored, particularly the role of chelation of heavy metals.

scholarly journals The role of heat shock proteins in kidney disease

2016 ◽  
Vol 4 (3) ◽  
pp. 114-117 ◽  
Author(s):  
Shobhana Nayak Rao
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Neurodegenerative Disorders ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Protective Role ◽  
The Family ◽  
Intracellular Proteins ◽  
Shock Proteins

AbstractHeat Shock Proteins (HSP) belong to the family of intracellular proteins that are constitutively expressed and are upregulated by various stressors including heat, oxidative and chemical stress. HSP helps in reparative processes, including the refolding of damaged proteins and the removal of irreparably damaged proteins that would initiate cellular death or apoptosis. A growing body of evidence has expanded the role of HSP and defined their role in diseases such as neurodegenerative disorders, cancer, ischemic heart disease and kidney diseases. The protective role of HSP in ischemic renal injury has been described and HSP impairment has been noted in other forms of kidney injuries including post-transplant situation. Further research into the role of HSP in prevention of kidney injury is crucial if translation from the laboratory to patient bedside has to occur. This article aims to be a review of heat shock protein, and its relevance to kidney diseases.

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