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Bioscience Reports Feb 2021Ferroptosis, a novel type of programmed cell death, is involved in inflammation and oxidation of various human diseases, including diabetic kidney disease. The present...
Ferroptosis, a novel type of programmed cell death, is involved in inflammation and oxidation of various human diseases, including diabetic kidney disease. The present study explored the role of high-mobility group box-1 (HMGB1) on the regulation of ferroptosis in mesangial cells in response to high glucose. Compared with healthy control, levels of serum ferritin, lactate dehydrogenase (LDH), reactive oxygen species (ROS), malonaldehyde (MDA), and HMGB1 were significantly elevated in diabetic nephropathy (DN) patients, accompanied with deregulated ferroptosis-related molecules, including long-chain acyl-CoA synthetase 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), NADPH oxidase 1 (NOX1), and glutathione peroxidase 4 (GPX4). In vitro assay revealed that erastin and high glucose both induced ferroptosis in mesangial cells. Suppression of HMGB1 restored cellular proliferation, prevented ROS and LDH generation, decreased ACSL4, PTGS2, and NOX1, and increased GPX4 levels in mesangial cells. Furthermore, nuclear factor E2-related factor 2 (Nrf2) was decreased in DN patients and high glucose-mediated translocation of HMGB1 in mesangial cells. Knockdown of HMGB1 suppressed high glucose-induced activation of TLR4/NF-κB axis and promoted Nrf2 expression as well as its downstream targets including HO-1, NQO-1, GCLC, and GCLM. Collectively, these findings suggest that HMGB1 regulates glucose-induced ferroptosis via Nrf2 pathway in mesangial cells.
Topics: Cell Line; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Ferroptosis; Glomerular Mesangium; Glucose; HMGB1 Protein; Humans; Male; Middle Aged; NF-E2-Related Factor 2; Oxidative Stress
PubMed: 33565572
DOI: 10.1042/BSR20202924 -
The Journal of Medical Investigation :... Feb 2004The renal glomerulus is composed of three types of glomerular cells (mesangial cell (MC), endothelial cell and podocyte) and extracellular matrix (ECM) consisting of the... (Review)
Review
The renal glomerulus is composed of three types of glomerular cells (mesangial cell (MC), endothelial cell and podocyte) and extracellular matrix (ECM) consisting of the glomerular basement membrane (GBM) and mesangial matrix. It constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. The proliferation of MCs, an increase of mesangial ECM and detachment podocyte from GBM are key biological features of progressive glomerulonephritis (GN), leading to glomerular scarring and dysfunction. Thus, the study of the molecular and cellular mechanisms responsible for pathological glomerular alterations may help to elucidate the pathogenesis of progressive glomerular diseases. A growing body of evidence indicates that beta1 integrin family (beta1 integrins), that mainly mediates cell adhesion to ECM, controls cell behaviors such as cell migration, proliferation, apoptosis and ECM assembly. In addition, a correlation between glomerular expression of beta1 integrins and their ligand ECM components is observed in various human and experimental GN, suggesting that altered beta1 integrins-mediated cell behaviors may contribute to the progression of GN. It is now becoming apparent that the expression of glomerular beta1 integrins is not only critical for maintaining the glomerular capillary permeability but it modulates cell signaling pathways regulating the cell phenotypes involved in the progression of glomerular diseases.
Topics: Animals; Extracellular Matrix; Glomerular Mesangium; Glomerulonephritis; Humans; Integrin beta1; Kidney Glomerulus; Models, Biological; Signal Transduction
PubMed: 15000250
DOI: 10.2152/jmi.51.1 -
Journal of Nephrology Feb 2016Immunoglobulin A nephropathy (IgAN) is characterized by the deposition of IgA in the mesangium of glomeruli. This mesangial IgA has been found to consist mainly of... (Review)
Review
Immunoglobulin A nephropathy (IgAN) is characterized by the deposition of IgA in the mesangium of glomeruli. This mesangial IgA has been found to consist mainly of polymeric IgA1 which drives the activation of the mesangial cells and results in excessive production of several inflammatory mediators. The activation of mesangial cells is amplified by the ability of IgA to activate the complement system, originally thought to occur mainly via the alternative pathway of complement. However more recent studies indicate that lectin pathway involvement has a strong association with progression of renal disease. In this review we summarize the contribution of complement to the IgA- mediated inflammatory process.
Topics: Animals; Complement Activation; Complement System Proteins; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Signal Transduction
PubMed: 26567162
DOI: 10.1007/s40620-015-0245-6 -
American Journal of Physiology. Renal... Oct 2003Mesangial cells (MCs) play a central role in the physiology and pathophysiology of endothelin-1 (ET-1) in the kidney. MCs release ET-1 in response to a variety of... (Review)
Review
Mesangial cells (MCs) play a central role in the physiology and pathophysiology of endothelin-1 (ET-1) in the kidney. MCs release ET-1 in response to a variety of factors, many of which are elevated in glomerular injury. MCs also express ET receptors, activation of which leads to a complex signaling cascade with resultant stimulation of MC hypertrophy, proliferation, contraction, and extracellular matrix accumulation. MC ET-1 interacts with other important regulatory factors, including arachidonate metabolites, nitric oxide, and angiotensin II. Excessive stimulation of ET-1 production by, and activity in, MC is likely of pathogenic importance in glomerular damage in the setting of diabetes, hypertension, and glomerulonephritis. The recent introduction of ET antagonists, and possibly ET-converting enzyme inhibitors, into the clinical arena establishes the potential for new therapies for those diseases characterized by increased MC ET-1 actions. This review will examine our present understanding of how ET-1 is involved in mesangial function in health and disease. In addition, we will discuss the status of clinical trials using ET antagonists, which have only been conducted in nonrenal disease, as a background for advocating their use in diseases characterized by excessive MC-derived ET-1.
Topics: Animals; Endothelin-1; Endothelins; Gene Expression; Glomerular Mesangium; Humans; Kidney Diseases; Signal Transduction
PubMed: 12954590
DOI: 10.1152/ajprenal.00019.2003 -
The Tohoku Journal of Experimental... Jan 1992The glomerular mesangial cell is a specialized pericyte with multiple functional capabilities including contraction. Mesangial contraction may reduce the glomerular... (Review)
Review
The glomerular mesangial cell is a specialized pericyte with multiple functional capabilities including contraction. Mesangial contraction may reduce the glomerular filtration surface area and hence the ultrafiltration coefficient, Kf. Cultured mesangial cells convert arachidonic acid into biologically active eicosanoids which are either contractile (thromboxane A2 [TxA2], prostaglandin F2 alpha [PGE2 alpha]) or relaxant (PGE2, PGI2). The addition of TxA2 analogues, PGE2 or sulfidopeptide leukotrienes (LTC4 and LTD4) stimulated contraction of cultured mesangial cells with threshold responses at approximately 1 nM and maximum responses at 1 microM. PGE2 and PGI2 antagonized mesangial contraction induced by TxA2 analogues. Contraction was enhanced by inhibiting mesangial cyclooxygenase with nonsteroidal antiinflammatory drugs (NSAID). Contractile eicosanoids stimulated phospholipase C thereby elevating intracellular inositol trisphosphate and cytosolic free Ca2+ concentration ([Ca2+]i). Vasorelaxant prostanoids stimulated adenylate cyclase, increasing intracellular cyclic AMP. We conclude that eicosanoids control mesangial contractility by regulating [Ca2+]i and cAMP. NSAID increase mesangial reactivity by blocking the inhibitory effects of endogenous vasodilator eicosanoids, with potential consequences on glomerular hemodynamics.
Topics: Animals; Eicosanoids; Glomerular Mesangium; Humans; Signal Transduction
PubMed: 1412447
DOI: 10.1620/tjem.166.57 -
Kidney International Dec 1999Renal basement membrane components. Basement membranes are specialized extracellular matrices found throughout the body. They surround all epithelia, endothelia,... (Review)
Review
Renal basement membrane components. Basement membranes are specialized extracellular matrices found throughout the body. They surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They play particularly important roles in the kidney, as demonstrated by the fact that defects in renal basement membranes are associated with kidney malfunction. The major components of all basement membranes are laminin, collagen IV, entactin/nidogen, and sulfated proteoglycans. Each of these describes a family of related proteins that assemble with each other in the extracellular space to form the basement membrane. Over the last few years, new basement membrane components that are expressed in the kidney have been discovered. Here, the major components and their localization in mature and developing renal basement membranes are described. In addition, the phenotypes of basement membrane component gene mutations, both naturally occurring and experimental, are discussed, as is the aberrant deposition of basement membrane proteins in the extracellular matrix in several renal diseases.
Topics: Animals; Basement Membrane; Extracellular Matrix; Glomerular Mesangium; Humans; Kidney Tubules
PubMed: 10594777
DOI: 10.1046/j.1523-1755.1999.00785.x -
Kidney International Mar 2002Nitric oxide and apoptosis in mesangial cells. Radicals such as nitric oxide (NO) or superoxide (O(-)(2)) encompass the ability to initiate morphological and biochemical... (Review)
Review
Nitric oxide and apoptosis in mesangial cells. Radicals such as nitric oxide (NO) or superoxide (O(-)(2)) encompass the ability to initiate morphological and biochemical alterations that are reminiscent of apoptosis. In mesangial cells, death as a result of NO formation is efficiently antagonized by the simultaneous presence of superoxide (O(-)(2)) and vice versa. This article reviews the consequences of a diffusion controlled NO/O(-)(2) interaction with the outcome of redirecting the apoptotic initiating activity of either NO or O(-)(2) toward protection. The crosstalk between cell destructive and protective pathways, and their activation or inhibition under the modulatory influence of NO and/or O(-)(2) are summarized.
Topics: Animals; Apoptosis; Glomerular Mesangium; Humans; Nitric Oxide; Reactive Oxygen Species
PubMed: 11849426
DOI: 10.1046/j.1523-1755.2002.00221.x -
American Journal of Physiology. Renal... Feb 2000The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that... (Review)
Review
The podocyte is the most differentiated cell type in the glomerulum, which forms a crucial component of the glomerular filtration barrier. It has been assumed that podocyte foot processes counteract the elastic force of the glomerular basement membrane and that vasoactive hormones may regulate the contractile state of their foot processes and thereby modulate the ultrafiltration coefficient K(f). Podocyte damage leads to proteinuria, and podocyte injury occurs in many glomerular diseases, which may progress to chronic renal failure. The understanding of the regulation of physiological properties of the podocyte and the mechanisms of its cellular response to injury may thus provide a clue to the understanding of the pathogenesis of proteinuria and glomerular diseases. In the past it was difficult to study cellular functions in this cell type, because of its unique anatomic location and the difficulty in characterizing podocytes in cell culture. However, recent advances in physiological, molecular biological, and cell culture techniques have increased the knowledge of the role of the podocyte in glomerular function. The present review attempts to outline new aspects of podocyte function in the glomerulum.
Topics: Adenosine Triphosphate; Angiotensin II; Animals; Cells, Cultured; Glomerular Mesangium; Humans; Neuropeptides; Receptors, Cell Surface; Signal Transduction
PubMed: 10662721
DOI: 10.1152/ajprenal.2000.278.2.F173 -
Kidney International Jun 1996Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell... (Review)
Review
Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell behavior, including cellular responses to soluble regulator molecules. In addition to the long-recognized role of such interactions in cell localization, anchoring and differentiation during embryogenesis, they are also involved in diverse processes such as maintenance of tissue integrity, response of cells to mechanical stress, inflammatory response, wound healing, tumor cell growth and metastasis as well as apoptosis. Over the last several years, evidence has been reported that extensive "cross-talk" between glomerular mesangial cells (MCs), ECM molecules and soluble mediator substances also affects the proliferative and synthetic phenotype of MCs. This is likely to be relevant for the behavior of MCs during embryonic development, tissue repair and disease processes of glomeruli. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus makes their elucidation a challenging goal in current kidney research. In this brief review, we present selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs. In addition to results from cell culture studies, descriptive findings on abnormalities of the ECM and their potential role for the altered MC behavior in glomerular disease will also be discussed.
Topics: Animals; Cell Adhesion; Extracellular Matrix; Glomerular Mesangium; Humans
PubMed: 8743458
DOI: 10.1038/ki.1996.228 -
Kidney International Jun 1996Among the multiple functions of the mesangial cell in glomerular physiology and pathophysiology, those of structural support of the capillary network, of participation... (Review)
Review
Among the multiple functions of the mesangial cell in glomerular physiology and pathophysiology, those of structural support of the capillary network, of participation in filtration regulation and in glomerular injury have attracted considerable interest. These roles are supported by studies with anti-Thy 1.1 antibody induced mesangiolysis in rats and by genetic knockout experiments of PDGF or PDGF-receptors in mice. These mice show a lack of mesangial cell development and a concomitant failure to establish a glomerular capillary network. Micropuncture experiments in the rats with mesangiolysis also provide support for a role of mesangial cells in the regulation of glomerular filtation. Numerous studies have established a contribution of mesangial cells to immunological and non-immunological injury in the glomerulus. Under many conditions this involves the recruitment and activation of macrophages, which require generation of chemotactic peptides and expression of adhesion molecules. Stimulation of mesangial cells with immune complexes and proinflammatory cytokines such as TNF-alpha or IL-1 results in the release of chemokines and in the appearance of adhesion molecules on the mesangial cells. The generation of reactive oxygen species appears to play a major role in this context and involves, at least in part, the activation of the transcription factor NF-kappa B. These results point toward mesangial cells as important participants in glomerular injury.
Topics: Animals; Glomerular Mesangium; Kidney Glomerulus
PubMed: 8743459
DOI: 10.1038/ki.1996.229