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Molecular Medicine (Cambridge, Mass.) Oct 2023Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration... (Review)
Review
Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.
Topics: Humans; Diabetic Nephropathies; Podocytes; Cell Death; Apoptosis; Epithelial Cells; Diabetes Mellitus
PubMed: 37828444
DOI: 10.1186/s10020-023-00732-4 -
Kidney Diseases (Basel, Switzerland) Aug 2023Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various... (Review)
Review
BACKGROUND
Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various stress conditions is the primary pathogenesis and key determinant of focal segmental glomerulosclerosis (FSGS) with prominent clinical manifestations of proteinuria or nephrotic syndrome.
SUMMARY
Under physiological conditions, a highly coordinated mitochondrial quality control system, including antioxidant defenses, mitochondrial dynamics (fusion, fission, and mitophagy), and mitochondrial biogenesis, guarantees the sophisticated structure and various functions of podocytes. However, under FSGS pathological conditions, mitochondria encounter oxidative stress, dynamics disturbances, and defective mitochondrial biogenesis. Moreover, mutations in mitochondrial DNA and mitochondria-related genes are also strongly associated with FSGS. Based on these pieces of evidence, bioactive agents that function to relieve mitochondrial oxidative stress and promote mitochondrial biogenesis have been proven effective in preclinical FSGS models. Targeting the mitochondrial network is expected to provide new therapeutic strategies for the treatment of FSGS and delay its progression to end-stage renal disease.
KEY MESSAGES
Mitochondrial dysfunction plays a key role in podocyte injury and FSGS progression. This review summarized recent advances in the study of mitochondrial homeostatic imbalance and dysfunction in FSGS and discussed the potential of mitochondria-targeted therapeutics in improving FSGS and retarding its progression to end-stage renal disease.
PubMed: 37900001
DOI: 10.1159/000530344 -
Nutrients Oct 2023Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function,...
Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function, causing proteinuria, altered fluid and electrolyte balances, and hypoalbuminemia [...].
Topics: Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Epithelial Cells
PubMed: 37960268
DOI: 10.3390/nu15214615 -
International Immunopharmacology Sep 2023Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the...
Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the primary active ingredient of T. wilfordii, effective in treating DN renal injury; however, the mechanisms underlying its effect are unclear. We explored how celastrol prevents DN podocyte damage using in vivo and in vitro experiments. We randomly divided 24 male C57BLKS/J mice into three groups: db/m (n = 8), db/db (n = 8), and celastrol groups (db/db + celastrol, 1 mg/kg/d, gavage administration, n = 8). In vivo experiments lasted 12 weeks and intervention lasted ten weeks. Serum samples and kidney tissues were collected for biochemical tests, pathological staining, transmission electron microscopy, fluorescencequantitation polymerase chain reaction, and western blotting analysis. In vitro experiments to elaborate the mechanism of celastrol protection were performed on high glucose (HG)-induced podocyte injury. Celastrol reduced blood glucose levels and renal function index in db/db mice, attenuated renal histomorphological injury and glomerular podocyte foot injuries, and induced significant anti-inflammatory effects. Celastrol upregulated silent information regulator 2 related enzyme 1(SIRT1) expression and downregulated enhancer of zeste homolog (EZH2), inhibiting the wnt/β-catenin pathway-related molecules, such as wnt1, wnt7a, and β-catenin. SIRT1 repressed the promoter activity of EZH2, and was co-immunoprecipitated with EZH2 in mouse podocyte cells (MPC5). SIRT1 knockdown aggravated the protective effects of celastrol on MPC5 cells. Celastrol protected podocyte injury via SIRT1/EZH2, which participates in the wnt/β-catenin pathway. Overall, celastrol-mediated SIRT1 upregulation inhibited the EZH2-related wnt/β-catenin signaling pathway to attenuate DN and podocyte injury, providing a theoretical basis for celastrol clinical application.
Topics: Mice; Male; Animals; Diabetic Nephropathies; Wnt Signaling Pathway; beta Catenin; Sirtuin 1; Podocytes; Proteinuria; Diabetes Mellitus
PubMed: 37454630
DOI: 10.1016/j.intimp.2023.110584 -
Metabolism: Clinical and Experimental Jan 2024Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of...
BACKGROUND AND AIMS
Podocyte injury is considered as the most important early event contributing to diabetic kidney disease (DKD). Recent findings provide new insights into the roles of lipids and lipid-modulating proteins as key determinants of podocyte function in health and kidney disease. CCDC92, a novel member of coiled-coil domain-containing protein family, was indicated relevant to lipid metabolism, coronary heart disease and type 2 diabetes. However, the expression pattern and role of CCDC92 in the kidney is not clear. This study was designed to elucidate the contribution of CCDC92 in the pathogenesis of DKD.
METHODS
Sections with a pathological diagnosis of different classes of DKD, including subjects with mild DKD (class II, n = 6), subjects with moderate DKD (class III, n = 6) or subjects with severe DKD (class IV, n = 6), and control samples (n = 12) were detected for the expression level of CCDC92 and lipid accumulation. Two types of diabetic mice model (db/db and HFD/STZ) in podocyte-specific Ccdc92 knockout background were generated to clarify the role of CCDC92 in podocyte lipotoxicity.
RESULTS
The level of CCDC92 was increased in renal biopsies sections from patients with DKD, which was correlated with eGFR and lipid accumulation in glomeruli. In animal studies, CCDC92 were also induced in the kidney from two independent diabetic models, especially in podocytes. Podocyte-specific deletion of Ccdc92 ameliorated podocyte injury and ectopic lipid deposition under diabetic condition. Mechanically, CCDC92 promoted podocyte lipotoxicity, at least in part through ABCA1 signaling-mediated lipid homeostasis.
CONCLUSION
Our studies demonstrates that CCDC92 acts as a novel regulator of lipid homeostasis to promote podocyte injury in DKD, suggesting that CCDC92 might be a potential biomarker of podocyte injury in DKD, and targeting CCDC92 may be an effective innovative therapeutic strategy for patients with DKD.
Topics: Animals; Humans; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Podocytes; Cytoskeletal Proteins; Lipid Metabolism
PubMed: 37952690
DOI: 10.1016/j.metabol.2023.155724 -
American Journal of Physiology. Renal... Dec 2023The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been... (Review)
Review
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of , resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
Topics: Mice; Humans; Animals; Nephrosis, Lipoid; Podocytes; Common Cold; Proteinuria; Glomerular Basement Membrane; Recurrence; Nephrotic Syndrome; Transcription Factors; Homeodomain Proteins
PubMed: 37795536
DOI: 10.1152/ajprenal.00219.2023 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023A ketogenic diet limits energy supply from glucose and stimulates lipolysis, lipid oxidation, and ketogenesis, resulting in elevated levels of ketone bodies in the... (Review)
Review
A ketogenic diet limits energy supply from glucose and stimulates lipolysis, lipid oxidation, and ketogenesis, resulting in elevated levels of ketone bodies in the bloodstream. Ketone bodies are synthesized in the mitochondrial matrix of liver cells and β-hydroxybutyric acid (BHB) is the most abundant type of ketone body. Herein, we reviewed published findings on the metabolism of ketone bodies and the role of BHB in renal diseases. Through blood circulation, ketone bodies reach metabolically active tissues and provides an alternative source of energy. BHB, being a signaling molecule, mediates various types of cellular signal transduction and participates in the development and progression of many diseases. BHB also has protective and therapeutic effects on a variety of renal diseases. BHB improves the prognosis of renal diseases, such as diabetic kidney disease, chronic kidney disease, acute kidney injury, and polycystic kidney disease, through its antioxidant, anti-inflammatory, and stress response mechanisms. Previous studies have focused on the role of ketone bodies in regulating inflammation and oxidative stress in immune cells. Investigations into the effect of elevated levels of ketone bodies on the metabolism of renal podocytes and tubular cells remain inconclusive. Further research is needed to investigate the effect of BHB on podocyte damage and podocyte senescence in renal diseases.
Topics: Humans; Ketone Bodies; 3-Hydroxybutyric Acid; Oxidative Stress; Antioxidants; Kidney; Kidney Diseases
PubMed: 38162055
DOI: 10.12182/20231160202 -
Free Radical Biology & Medicine Jul 2023Defective antioxidant system as well as mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor...
Defective antioxidant system as well as mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling is the central defensive mechanism against oxidative stress and therefore pharmacological activation of Nrf2 is a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula of Huangqi decoction (HQD), exerted a higher potential to promote Nrf2 escape from Keap1-Nrf2 interaction via competitively bind to amino acid sites in Keap1. When podocyte exposed to high glucose (HG) stimulation, mitochondrial morphological alterations and podocyte apoptosis were presented and accompanied by Nrf2 and mitochondrial transcription factor A (TFAM) downregulation. Mechanistically, HG promoted a decrease in mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis and mtDNA content as well as increased ROS production. Conversely, all these mitochondrial defects were dramatically alleviated by AS-IV, but suppression of Nrf2 with inhibitor or siRNA and TFAM siRNA simultaneously alleviated the AS-IV efficacy. Moreover, experimental diabetic mice exhibited significant renal injury as well as mitochondrial disorder, corresponding with the decreased expression of Nrf2 and TFAM. On the contrary, AS-IV reversed the abnormality and the Nrf2 and TFAM expression were also restored. Taken together, the present findings demonstrate the improvement of AS-IV on mitochondrial function, thereby resistance to oxidative stress-induced diabetic kidney injury and podocyte apoptosis, and the process is closely associated with activation of Nrf2-ARE/TFAM signaling.
Topics: Mice; Animals; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Diabetic Nephropathies; Podocytes; Diabetes Mellitus, Experimental; Molecular Docking Simulation; Oxidative Stress; Mitochondria; Apoptosis; RNA, Small Interfering; DNA-Binding Proteins; High Mobility Group Proteins
PubMed: 37030337
DOI: 10.1016/j.freeradbiomed.2023.03.022 -
The American Journal of the Medical... Dec 2023Angiogenesis and immunosuppression are closely related pathophysiologic processes. Widely prescribed in malignant tumor and proliferative retinal lesions, VEGF signaling... (Review)
Review
Angiogenesis and immunosuppression are closely related pathophysiologic processes. Widely prescribed in malignant tumor and proliferative retinal lesions, VEGF signaling pathway inhibitors may cause hypertension and renal injury in some patients, presenting with proteinuria, nephrotic syndrome, renal failure and thrombotic microangiopathy. VEGF signaling pathway inhibitors block the action of both VEGF-A and VEGF-C. However, VEGF-A and VEGF-C produced by podocytes are vital to maintain the physiological function of glomerular endothelial cells and podocytes. There is still no effective treatment for kidney disease associated with VEGF signaling pathway inhibitors and some patients have progressive renal failure even after withdrawal of the drug. Recent studies reveal that blocking of VEGF-A and VEGF-C can activate CD4 and CD8 T cells, augment antigen-presenting function of dendritic cells, enhance cytotoxicity of macrophages and initiate complement cascade activation. VEGF and VEGFR are expressed in immune cells, which are involved in the immunosuppression and cross-talk among immune cells. This review summarizes the expression and function of VEGF-A and VEGF-C in the kidney. The current immunoregulation mechanisms of VEGF signaling pathway inhibitors are reviewed. Finally, combinate strategies are summarized to highlight the proposal for VEGF signaling pathway inhibitors.
Topics: Humans; CD8-Positive T-Lymphocytes; Endothelial Cells; Kidney; Renal Insufficiency; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C
PubMed: 37699444
DOI: 10.1016/j.amjms.2023.09.005 -
Kidney360 Sep 2023Since the seminal discovery of the trypanolytic, exonic variants in apolipoprotein L1 (APOL1) and their association with kidney disease in individuals of recent African... (Review)
Review
Since the seminal discovery of the trypanolytic, exonic variants in apolipoprotein L1 (APOL1) and their association with kidney disease in individuals of recent African ancestry, a wide body of research has emerged offering key insights into the mechanisms of disease. Importantly, the podocyte has become a focal point for our understanding of how risk genotype leads to disease, with activation of putative signaling pathways within the podocyte identified as playing a causal role in podocytopathy, FSGS, and progressive renal failure. However, the complete mechanism of genotype-to-phenotype progression remains incompletely understood in APOL1-risk individuals. An emerging body of evidence reports more than podocyte-intrinsic expression of APOL1 risk variants is needed for disease to manifest. This article reviews the seminal data and reports which placed the podocyte at the center of our understanding of APOL1-FSGS, as well as the evident shortcomings of this podocentric paradigm. We examine existing evidence for environmental and genetic factors that may influence disease, drawing from both clinical data and APOL1's fundamental role as an immune response gene. We also review the current body of data for APOL1's impact on nonpodocyte cells, including endothelial cells, the placenta, and immune cells in both a transplant and native setting. Finally, we discuss the implications of these emerging data and how the paradigm of disease might evolve as a result.
Topics: Humans; Glomerulosclerosis, Focal Segmental; Apolipoprotein L1; Risk Factors; Endothelial Cells; Genotype
PubMed: 37461136
DOI: 10.34067/KID.0000000000000216