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Pediatric Nephrology (Berlin, Germany) Sep 2021The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells,... (Review)
Review
The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells, the glomerular basement membrane, and podocytes. Functional impairment or injury of any of these three components can lead to proteinuria. Podocytes are injured in many forms of human and experimental glomerular disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetes mellitus. One of the earliest signs of podocyte injury is loss of their distinct structure, which is driven by dysregulated dynamics of the actin cytoskeleton. The status of the actin cytoskeleton in podocytes depends on a set of actin binding proteins, nucleators and inhibitors of actin polymerization, and regulatory GTPases. Mutations that alter protein function in each category have been implicated in glomerular diseases in humans and animal models. In addition, a growing body of studies suggest that pharmacological modifications of the actin cytoskeleton have the potential to become novel therapeutics for podocyte-dependent chronic kidney diseases. This review presents an overview of the essential proteins that establish actin cytoskeleton in podocytes and studies demonstrating the feasibility of drugging actin cytoskeleton in kidney diseases.
Topics: Actin Cytoskeleton; Animals; Humans; Podocytes
PubMed: 33188449
DOI: 10.1007/s00467-020-04812-z -
Kidney International Jul 2022Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte...
Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.
Topics: Animals; Doxorubicin; Glomerulosclerosis, Focal Segmental; Humans; Hypertrophy; Mammals; Mice; Phosphorylation; Podocytes; Protein Serine-Threonine Kinases; Ribosomal Protein S6
PubMed: 35483522
DOI: 10.1016/j.kint.2022.02.037 -
Molecular Medicine (Cambridge, Mass.) Oct 2023It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for...
BACKGROUND
It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI.
METHODS
This study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin-eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins-solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)-as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro.
RESULTS
Kidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro.
CONCLUSION
Our findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis.
Topics: Mice; Animals; Cisplatin; Ferroptosis; Podocytes; Chemokine CX3CL1; Mice, Knockout; Acute Kidney Injury; Kidney
PubMed: 37875838
DOI: 10.1186/s10020-023-00733-3 -
Journal of the American Society of... Dec 2022
Topics: Humans; Intercellular Junctions; Glomerulosclerosis, Focal Segmental; Sleep; Podocytes
PubMed: 36332973
DOI: 10.1681/ASN.2022101147 -
Biomedicine & Pharmacotherapy =... Sep 2021Microparticles are a general term for different types of cell plasma membrane-originated vesicles that are released into the extracellular environment. The paracrine... (Review)
Review
Microparticles are a general term for different types of cell plasma membrane-originated vesicles that are released into the extracellular environment. The paracrine action of these nano-sized vesicles is crucial for intercellular communications through the transfer of diverse lipids, cytosolic proteins, RNA as well as microRNAs. The progression of different diseases influences the composition, occurrence, and functions of these cell-derived particles. Podocyte injury has been shown to have an important role in the pathophysiology of many glomerular diseases including IgA nephropathy (IgAN). This review would focus on the possible potential of podocyte-derived microparticles detected in urine to be used as a diagnostic tool in IgAN.
Topics: Animals; Cytoplasmic Vesicles; Glomerulonephritis, IGA; Humans; MicroRNAs; Nanoparticles; Podocytes
PubMed: 34237594
DOI: 10.1016/j.biopha.2021.111891 -
Cell Biology International Jan 2022Podocytes, highly specified kidney epithelial cells, live under several pathological stimuli and stresses during which they adapt themselves to keep homeostasis.... (Review)
Review
Podocytes, highly specified kidney epithelial cells, live under several pathological stimuli and stresses during which they adapt themselves to keep homeostasis. Nevertheless, under extreme stress, a complex scenario of podocyte damage and its consequences occur. Podocyte damage causes foot process effacement and their detachment from the glomerular basement membrane, leading to proteinuria. Podocyte-derived extracellular vesicles (pEVs), mainly microparticles and exosomes are considered as signaling mediators of intercellular communication. Recently, it has been shown that throughout the injury-related migration procedure, podocytes are capable of releasing the injury-related migrasomes. Evidence indicates that at the early stages of glomerular disorders, increased levels of pEVs are observed in urine. At the early stage of nephropathy, pEVs especially migrasomes seem to be more sensitive and reliable indicators of podocyte stress and/or damage than proteinuria. This review highlights the current knowledge of pEVs and their values for the diagnosis of different kidney diseases.
Topics: Animals; Biomarkers; Cell Communication; Cell Movement; Exosomes; Humans; Kidney; Kidney Diseases; Podocytes; Signal Transduction
PubMed: 34647672
DOI: 10.1002/cbin.11711 -
Nature Reviews. Nephrology Dec 2019Idiopathic nephrotic syndrome (INS) describes a group of pathologies of the renal glomerulus that result in the classic triad of heavy proteinuria, oedema and... (Review)
Review
Idiopathic nephrotic syndrome (INS) describes a group of pathologies of the renal glomerulus that result in the classic triad of heavy proteinuria, oedema and hypoalbuminaemia. The disease has historically been defined by evidence of distinctive histological changes in the absence of clinical evidence of a distinct pathological driver. However, the current classification is not based on any systematic mechanistic understanding of biological processes, and therefore current treatment regimens are broad, iterative and nonspecific. Over the past 20 years delineation of the underlying biology of the target cell in INS - the glomerular podocyte - has transformed our understanding of the mechanisms that contribute to breakdown of the glomerular filtration barrier and the development of INS. It is increasingly clear that nephrotic syndrome caused by monogenic mutations is distinct from immune-driven disease, which in some cases is mediated by circulating factors that target the podocyte. The combination of systems biology and bioinformatics approaches, together with powerful laboratory models and ever-growing patient registries has potential to identify disease 'signatures' that reflect the underlying molecular mechanism of INS on an individual basis. Understanding of such processes could lead to the development of targeted therapies.
Topics: Humans; Nephrotic Syndrome; Podocytes; Signal Transduction
PubMed: 31654044
DOI: 10.1038/s41581-019-0217-5 -
International Journal of Molecular... Jun 2020Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian...
Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.
Topics: Animals; Apoptosis; Biomarkers; Disease Models, Animal; Doxorubicin; Gene Expression; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Kidney Diseases; MAP Kinase Signaling System; Mice; Podocytes; Proteinuria; Semaphorin-3A
PubMed: 32521824
DOI: 10.3390/ijms21114099 -
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 -
American Journal of Physiology. Renal... Apr 2022The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical...
The podocyte is an important component of the glomerular filtration barrier, and maintenance of the integrity of its highly specified structure and function is critical for normal kidney function. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are two crucial effectors of the Hippo signaling pathway, and recent studies have shown that podocyte-specific YAP deletion causes podocyte apoptosis and the development of focal segmental glomerulosclerosis followed by progressive renal failure. In the present study, we investigated a potential role of the YAP paralog TAZ in podocytes. TAZ was found to be constitutively active in podocytes, and mice with podocyte-specific deletion of TAZ () developed proteinuria starting at 4 wk of age and had increased podocyte apoptosis. Using primary cultured podocytes or immortalized mouse podocytes from mice, we found that TAZ is a transcriptional activator for TEAD-dependent expression of synaptopodin, zonula occludens-1, and zonula occludens-2. This is the first study to determine that TAZ plays an important role in the maintenance of the structure and function of podocytes. Podocytes play an important role in maintaining the integrity of the structure and function of the kidney. We observed that mice with selective deletion of transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes developed proteinuria. TAZ is constitutively active and critical for expression of synaptopodin, zonula occludens-1, and zonula occludens-2 in podocytes. The findings of this study implicate TAZ as an important mediator of podocyte structural integrity and provide further insights into the role of Hippo-Yes-associated protein/TAZ in podocyte biology.
Topics: Animals; Glomerulosclerosis, Focal Segmental; Kidney; Mice; Podocytes; Proteinuria; Transcription Factors
PubMed: 35157550
DOI: 10.1152/ajprenal.00426.2021