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Kidney International Mar 2024Complement activation has long been recognized as a central feature of membranous nephropathy (MN). Evidence for its role has been derived from the detection of... (Review)
Review
Complement activation has long been recognized as a central feature of membranous nephropathy (MN). Evidence for its role has been derived from the detection of complement products in biopsy tissue and urine from patients with MN and from mechanistic studies primarily based on the passive Heymann nephritis model. Only recently, more detailed insights into the exact mechanisms of complement activation and effector pathways have been gained from patient data, animal models, and in vitro models based on specific target antigens relevant to the human disease. These data are of clinical relevance, as they parallel the recent development of numerous specific complement therapeutics for clinical use. Despite efficient B-cell depletion, many patients with MN achieve only partial remission of proteinuria, which may be explained by the persistence of subepithelial immune complexes and ongoing complement-mediated podocyte injury. Targeting complement, therefore, represents an attractive adjunct treatment for MN, but it will need to be tailored to the specific complement pathways relevant to MN. This review summarizes the different lines of evidence for a central role of complement in MN and for the relevance of distinct complement activation and effector pathways, with a focus on recent developments.
Topics: Animals; Humans; Glomerulonephritis, Membranous; Complement Activation; Podocytes; Complement System Proteins; Antigen-Antibody Complex
PubMed: 38142037
DOI: 10.1016/j.kint.2023.10.035 -
Advances in Clinical Chemistry 2022The discovery of nephrin in 1998 has launched a new era in glomerular diseases research, emphasizing its crucial role in the structure and function of the glomerular...
The discovery of nephrin in 1998 has launched a new era in glomerular diseases research, emphasizing its crucial role in the structure and function of the glomerular filtration barrier. In the past 20 years, substantial advances have been made in understanding podocyte structure and function as well as the discovery of several podocyte-related proteins including nephrin. The glomerular filtration barrier is comprised of podocytes, the glomerular basement membrane and endothelial cells. Podocytes, with their specialized slit diaphragm, form the essential backbone of the glomerular filtration barrier. Nephrin is a crucial structural and functional feature of the slit diaphragm that prevents plasma protein, blood cell and macromolecule leakage into the urine. Podocyte damage results in nephrin release. Podocytopathies are kidney diseases in which podocyte damage drives proteinuria, i.e., nephrotic syndrome. Many kidney diseases involve podocytopathy including congenital nephrotic syndrome of Finnish type, diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulonephropathy, diabetic nephropathy, lupus nephropathy, hypertensive nephropathy and preeclampsia. Recently, urinary nephrin measurement has become important in the early detection of podocytopathies. In this chapter, we elaborate the main structural and functional features of nephrin as a podocyte-specific protein, pathomechanisms of podocytopathies which result in nephrinuria, highlight the most commonly used methods for detecting urinary nephrin and investigate the diagnostic, prognostic and potential therapeutic relevance of urinary nephrin in primary and secondary proteinuric kidney diseases.
Topics: Endothelial Cells; Humans; Kidney Diseases; Nephrotic Syndrome; Podocytes; Proteinuria
PubMed: 35659057
DOI: 10.1016/bs.acc.2021.08.001 -
Biomedicine & Pharmacotherapy =... Dec 2022Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot... (Review)
Review
Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot processes (FP) and their interposed slit diaphragms (SD) are the final barriers against protein loss. Podocyte effacement and the resultant deterioration of podocyte SD integrity that involve the active rearrangement of the podocyte actin cytoskeleton is a chief mechanism of proteinuric kidney diseases. The progress of these injuries can eventually lead to cell detachment and death. Due to the prominence of the actin cytoskeleton in maintaining glomerular filtration, the assessment of the molecular design and regulation of actin is a central target of podocyte research. In the current review, a comprehensive summary of the actin cytoskeleton, its constituents, and regulatory signaling pathways has been provided. Since actin-regulated cell plasticity is a crucial feature of normal podocyte function, and deteriorations in its dynamics seem to directly affect podocyte morphology and glomerular permeability, this review discusses cascades that regulate actin polymerization in podocytes.
Topics: Actins; Actin Cytoskeleton; Podocytes; Kidney Glomerulus; Intercellular Junctions
PubMed: 36411613
DOI: 10.1016/j.biopha.2022.113920 -
Kidney International Jul 2023The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein...
The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis.
Topics: Mice; Animals; Endothelial Cells; Epithelial Cells; Kidney Glomerulus; Podocytes; Glomerulonephritis; Proteins; Kidney Diseases
PubMed: 37100348
DOI: 10.1016/j.kint.2023.03.036 -
Kidney360 Mar 2022
Topics: Biomarkers; Humans; Kidney Glomerulus; Podocytes; Renal Insufficiency, Chronic; Urinary Tract
PubMed: 35582191
DOI: 10.34067/KID.0008212021 -
Kidney360 Apr 2021CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited.... (Review)
Review
CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.
Topics: Humans; Kidney; Kidney Glomerulus; Lipid Metabolism; Podocytes; Renal Insufficiency, Chronic
PubMed: 35373048
DOI: 10.34067/KID.0006152020 -
Clinica Chimica Acta; International... Dec 2021Podocytes play an important role in the maintenance of kidney function, and they are the primary focus of many kidney diseases. Podocyte injury results in the shedding... (Review)
Review
Podocytes play an important role in the maintenance of kidney function, and they are the primary focus of many kidney diseases. Podocyte injury results in the shedding of podocyte-derived cellular fragments and podocyte-specific molecular targets into the urine, which may serve as biomarkers of kidney diseases. Intact podocytes, either viable or dead, and podocyte-derived microvesicles could be quantified in the urine by various centrifugation, visualization and culture methods. Podocyte-specific protein targets from the nucleus, cytoplasm, slit-diaphragm, glomerular capillary basement membrane, and cytoskeleton, as well as their corresponding messenger RNA (mRNA), in the urine could be quantified by western blotting, ELISA, or quantitative polymerase chain reaction. Although some of these techniques may be expensive or labor-intensive at present, they may become widely available in the future because of the improvement in technology and automation. The application of urinary podocyte markers for the diagnosis and monitoring of various kidney diseases have been explored but the published data in this area are not sufficiently systematic and lack external validation. Further research should focus on standardizing, comparing, and automizing laboratory methods, as well as defining their added value to the routine clinical tests.
Topics: Biomarkers; Humans; Kidney Diseases; Kidney Glomerulus; Podocytes; RNA, Messenger
PubMed: 34666027
DOI: 10.1016/j.cca.2021.10.017 -
American Journal of Physiology. Renal... May 2023
Topics: Podocytes; Kidney Glomerulus
PubMed: 36892909
DOI: 10.1152/ajprenal.00045.2023 -
Biomolecules May 2022Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular... (Review)
Review
Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular ultrafiltration, vasodilation, and inflammation. Changes in NO bioavailability in pathophysiological conditions such as hypertension or diabetes may lead to podocyte damage, proteinuria, and rapid development of chronic kidney disease (CKD). Despite the extensive data highlighting essential functions of NO in health and pathology, related signaling in glomerular cells, particularly podocytes, is understudied. Several reports indicate that NO bioavailability in glomerular cells is decreased during the development of renal pathology, while restoring NO level can be beneficial for glomerular function. At the same time, the compromised activity of nitric oxide synthase (NOS) may provoke the formation of peroxynitrite and has been linked to autoimmune diseases such as systemic lupus erythematosus. It is known that the changes in the distribution of NO sources due to shifts in NOS subunits expression or modifications of NADPH oxidases activity may be linked to or promote the development of pathology. However, there is a lack of information about the detailed mechanisms describing the production and release of NO in the glomerular cells. The interaction of NO and other reactive oxygen species in podocytes and how NO-calcium crosstalk regulates glomerular cells' function is still largely unknown. Here, we discuss recent reports describing signaling, synthesis, and known pathophysiological mechanisms mediated by the changes in NO homeostasis in the podocyte. The understanding and further investigation of these essential mechanisms in glomerular cells will facilitate the design of novel strategies to prevent or manage health conditions that cause glomerular and kidney damage.
Topics: Humans; Kidney; Kidney Glomerulus; Nitric Oxide; Nitric Oxide Synthase; Podocytes; Proteinuria
PubMed: 35740870
DOI: 10.3390/biom12060745 -
Journal of the American Society of... Mar 2023The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains...
SIGNIFICANCE STATEMENT
The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury.
BACKGROUND
Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence.
METHODS
Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development.
RESULTS
Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine.
CONCLUSIONS
Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
Topics: Animals; Mice; Cell Cycle; Histone Deacetylase 1; Mice, Knockout; Podocytes; Proteinuria
PubMed: 36414418
DOI: 10.1681/ASN.2022050598