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American Journal of Physiology. Renal... Mar 2021Although macula densa (MD) cells are chief regulatory cells in the nephron with unique microanatomical features, they have been difficult to study in full detail due to...
Although macula densa (MD) cells are chief regulatory cells in the nephron with unique microanatomical features, they have been difficult to study in full detail due to their inaccessibility and limitations in earlier microscopy techniques. The present study used a new mouse model with a comprehensive imaging approach to visualize so far unexplored microanatomical features of MD cells, their regulation, and functional relevance. MD-GFP mice with conditional and partial induction of green fluorescent protein (GFP) expression, which specifically and intensely illuminated only single MD cells, were used with fluorescence microscopy of fixed tissue and live MD cells in vitro and in vivo with complementary electron microscopy of the rat, rabbit, and human kidney. An elaborate network of major and minor cell processes, here named maculapodia, were found at the cell base, projecting toward other MD cells and the glomerular vascular pole. The extent of maculapodia showed upregulation by low dietary salt intake and the female sex. Time-lapse imaging of maculapodia revealed highly dynamic features including rapid outgrowth and an extensive vesicular transport system. Electron microscopy of rat, rabbit, and human kidneys and three-dimensional volume reconstruction in optically cleared whole-mount MD-GFP mouse kidneys further confirmed the presence and projections of maculapodia into the extraglomerular mesangium and afferent and efferent arterioles. The newly identified dynamic and secretory features of MD cells suggest the presence of novel functional and molecular pathways of cell-to-cell communication in the juxtaglomerular apparatus between MD cells and between MD and other target cells. This study illuminated a physiologically regulated dense network of basal cell major and minor processes (maculapodia) in macula densa (MD) cells. The newly identified dynamic and secretory features of these microanatomical structures suggest the presence of novel functional and molecular pathways of cell-to-cell communication in the juxtaglomerular apparatus between MD and other target cells. Detailed characterization of the function and molecular details of MD cell intercellular communications and their role in physiology and disease warrant further studies.
Topics: Animals; Cell Communication; Epithelial Cells; Glomerular Mesangium; Juxtaglomerular Apparatus; Kidney Glomerulus; Kidney Tubules; Mice; Rabbits; Rats
PubMed: 33491562
DOI: 10.1152/ajprenal.00546.2020 -
Kidney360 Aug 2021IgA nephropathy (IgAn), defined by the pre dominant de position of IgA in the glomerular mesangium, is the most common form of GN throughout the world. However, its... (Review)
Review
IgA nephropathy (IgAn), defined by the pre dominant de position of IgA in the glomerular mesangium, is the most common form of GN throughout the world. However, its incidence, sex distribution, clinical presentation, and progression and pathogenic initiating factors are largely variable and do not fit such a simple definition. To assess the heterogeneity of this disease, we recently conducted a clinical survey on the presentation and clinical management of patients with IgAn in Europe and Japan. This clinical survey highlights similarities and differences in patients from different cont inents. The survey revealed obvious differences between nations in the frequency of gastrointestinal complications, including inflammatory bowel diseases (IBD) and celiac disease, which were more frequent in European patients. Such findings are compatible with susceptibility loci related to intestinal immunity and IBD in recent genome wide association studies (GWAS) on IgAn. However, most of the molecules in these mucosal-related loci fulfill the immunologic function not only of gut-associated lymphoid tissue (GALT), but also nasopharyngeal/bronchial-associated lymphoid tissues (NALT/BALT). Indeed, a similar frequency of macrohematuria coinciding with upper respiratory infection, a hallmark manifestation of this disease, was found in the survey, emphasizing the pathogenic roles of these molecules in the NALT/BALT of patients with IgAn. Recent experimental and clinical studies including GWAS on multiple common infections and IBD indicate immune crosstalk between GALT and NALT/BALT, and some related mediators, such as TNF superfamily ligands (APRIL/BAFF). This review explains the epidemiologic heterogeneity of this disease with the clinical survey, and discusses race and sex-dependent molecular mechanisms.
Topics: Celiac Disease; Genome-Wide Association Study; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunity, Mucosal
PubMed: 35369654
DOI: 10.34067/KID.0002972021 -
Proceedings of SPIE--the International... Feb 2020Diabetic Nephropathy (DN) progression is stratified into several stages with different levels of proteinuria, albuminuria, and physical characteristics as observed by...
Diabetic Nephropathy (DN) progression is stratified into several stages with different levels of proteinuria, albuminuria, and physical characteristics as observed by pathologists. These physical changes are primarily visible within a patient's glomeruli which function as filtration units for blood returning for oxygenation. As DN stage increases, it is possible to observe the thickening of the glomerular basement membrane, expansion of the mesangium, and development of nodular sclerosis. Classification of different stages of DN by pathologists is based on semi-qualitative assessments of these characteristics on an individual glomerulus basis. Being able to probabilistically infer stage membership of individual glomeruli based on a combination of easily observable and hidden image features would be an invaluable tool for furthering our understanding of the drivers of DN progression. Markov Particle filters, included in the package in R, were used to query a Bayesian Network (BN) constructed using the structural Hill-Climbing algorithm on a set of glomerular features. These features included both traditional characteristics such as glomerular area and number of mesangial nuclei as well as more abstract features derived from Minimum Spanning Trees (MST) to quantify spatial distribution of mesangial nuclei. Our results using images from multiple institutions suggest that these abstract features exercise a variable influence on DN stage membership over the course of disease progression. Further research incorporating clinical data will give nephrologists a "white box" visual of quantitative factors present in DN patients.
PubMed: 32382209
DOI: 10.1117/12.2549171 -
Experimental and Therapeutic Medicine Jul 2020Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is the main cause of end-stage renal disease. IgAN is characterized by the...
Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is the main cause of end-stage renal disease. IgAN is characterized by the accumulation of immune complexes in the circulation, which contain abnormal levels of IgA. IgAN primarily results from galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 deposition in the renal mesangium, causing local proliferation and matrix expansion. Gd-IgA1 has been confirmed as one of the key effectors in the pathogenesis of IgAN, but the origin of Gd-IgA1 is not clear. Recent studies have shown that Gd-IgA1 deposition could be the result of mucosally primed plasma cells and is associated with T cell dysregulation. T cells contribute to the IgA response and play an important role in the development of IgAN. In the present review, the latest discoveries regarding the role of T lymphocytes in the pathogenesis of IgAN have been summarized. Understanding these advances will allow novel therapeutic strategies for the treatment of IgAN.
PubMed: 32509008
DOI: 10.3892/etm.2020.8673 -
Frontiers in Medicine 2020IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with diverse clinical manifestations characterized by recurrent gross hematuria or... (Review)
Review
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with diverse clinical manifestations characterized by recurrent gross hematuria or microscopic hematuria, and pathological changes featuring poorly O-galactosylated IgA1 deposition in the glomerular mesangium. Pathogenesis has always been the focus of IgAN studies. After 50 years of research, most scholars agree that IgAN is a group of clinicopathological syndromes with certain common immunopathological characteristics, and multiple mechanisms are involved in its pathogenesis, including immunology, genetics, and environmental or nutritional factors. However, the precise pathogenetic mechanisms have not been fully determined. One hypothesis about the pathogenesis of IgAN suggests that immunological factors are engaged in all aspects of IgAN development and play a critical role. A variety of immune cells (e.g., dendritic cells, NK cells, macrophages, T-lymphocyte subsets, and B-lymphocytes, etc.) and molecules (e.g., IgA receptors, Toll-like receptors, complements, etc.) in innate and adaptive immunity are involved in the pathogenesis of IgAN. Moreover, the abnormality of mucosal immune regulation is the core of IgAN immunopathogenesis. The roles of tonsil immunity or intestinal mucosal immunity, which have received more attention in recent years, are supported by mounting evidence. In this review, we will explore the latest research insights on the role of immune modulation in the pathogenesis of IgAN. With a better understanding of immunopathogenesis of IgAN, emerging therapies will soon become realized.
PubMed: 32266276
DOI: 10.3389/fmed.2020.00092 -
Frontiers in Pediatrics 2021Cathepsin S (CTSS) is an important lysosomal cysteine protease. This study aimed at investigating the clinical significance of CTSS and underlying mechanism in...
Cathepsin S (CTSS) is an important lysosomal cysteine protease. This study aimed at investigating the clinical significance of CTSS and underlying mechanism in immunoglobulin A nephropathy (IgAN). This study recruited 25 children with IgAN and age-matched controls and their serum CTSS levels were measured by enzyme-linked immunosorbent assay (ELISA). Following induction of IgAN in rats, their kidney CTSS expression, IgA accumulation and serum CTSS were characterized by immunohistochemistry, immunofluorescence, and ELISA. The impact of IgA1 aggregates on the proliferation of human mesangial cells (HMCs) was determined by Cell Counting Kit-8 and Western blot analysis of Ki67. Compared to the non-IgAN controls, significantly up-regulated CTSS expression was detected in the renal tissues, particularly in the glomerular mesangium and tubular epithelial cells of IgAN patients, accompanied by higher levels of serum CTSS ( < 0.05), which were correlated with the levels of 24-h-urine proteins and microalbumin and urine erythrocytes and grades of IgAN Lee's classification in children with IgAN ( < 0.01 for all). Following induction of IgAN, we detected inducible IgA accumulation and increased levels of CTSS expression in the glomerular mesangium and glomerular damages in rats, which were mitigated by LY3000328, a CTSS-specific inhibitor. Treatment with LY3000328 significantly mitigated the Ki67 expression in the kidney of IgAN rats ( < 0.01) and significantly minimized the IgA1 aggregate-stimulated proliferation of HMCs and their Ki67 expression ( < 0.01). CTSS promoted the proliferation of glomerular mesangial cells, contributing to the pathogenesis of IgAN and may be a new therapeutic target for intervention of aberrant mesangial cell proliferation during the process of IgAN.
PubMed: 33912521
DOI: 10.3389/fped.2021.631473 -
Frontiers in Physiology 2020Diabetic nephropathy (DN) is an important public health concern of increasing proportions and the leading cause of end-stage renal disease (ESRD) in diabetic patients.... (Review)
Review
Diabetic nephropathy (DN) is an important public health concern of increasing proportions and the leading cause of end-stage renal disease (ESRD) in diabetic patients. It is one of the most common long-term microvascular complications of diabetes mellitus that is characterized by proteinuria and glomerular structural changes. Angiogenesis has long been considered to contribute to the pathogenesis of DN, whereas the molecular mechanisms of which are barely known. Angiogenic factors associated with angiogenesis are the major candidates to explain the microvascular and pathologic finds of DN. Vascular endothelial growth factor A (VEGF-A), leucine-rich α-2-glycoprotein 1, angiopoietins and vasohibin family signal between the podocytes, endothelium, and mesangium have important roles in the maintenance of renal functions. An appropriate amount of VEGF-A is beneficial to maintaining glomerular structure, while excessive VEGF-A can lead to abnormal angiogenesis. LRG1 is a novel pro-angiogenic factors involved in the abnormal angiogenesis and renal fibrosis in DN. The imbalance of Ang1/Ang2 ratio has a role in leading to glomerular disease. Vasohibin-2 is recently shown to be in diabetes-induced glomerular alterations. This review will focus on current understanding of these angiogenic factors in angiogenesis and pathogenesis associated with the development of DN, with the aim of evaluating the potential of anti-angiogenesis therapy in patients with DN.
PubMed: 32982792
DOI: 10.3389/fphys.2020.01064 -
Kidney International Reports Nov 2020Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light... (Review)
Review
Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain-derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, which include apoptosis, phenotype transformation, and secretion of extracellular matrix components and metalloproteinases. Monoclonal light chains associated with AL-Am but not those producing LCDD are avidly endocytosed by mesangial cells and delivered to the mature lysosomal compartment where amyloid fibrils are formed. Light chains from patients with LCDD exert their pathogenic signaling effect at the cell surface of mesangial cells. These events are generic mesangial responses to a variety of adverse stimuli, and they are similar to those characterizing other more frequent glomerulopathies responsible for many cases of end-stage renal disease. The pathophysiologic events that have been elucidated allow to propose future therapeutic approaches aimed at preventing, stopping, ameliorating, or reversing the adverse effects resulting from the interactions between glomerulopathic light chains and mesangium.
PubMed: 33163710
DOI: 10.1016/j.ekir.2020.07.013 -
American Journal of Physiology. Renal... Nov 2021Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E,...
Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: ) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and ) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis. Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.
Topics: Biopsy; Bowman Capsule; Capillaries; Capillary Permeability; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Fibrosis; Glomerular Basement Membrane; Glomerulonephritis; Humans; Microscopy, Electron, Transmission; Neovascularization, Pathologic; Nephrons; Podocytes
PubMed: 34541901
DOI: 10.1152/ajprenal.00669.2020 -
Clinical Journal of the American... Dec 2021IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in...
BACKGROUND AND OBJECTIVES
IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in both AKI and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. , human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by quantitative RT-PCR and immunofluorescence. The codeposition of collectin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays.
RESULTS
In total, 37% of participants with IgA nephropathy (22 of 60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface the interaction with deposited IgA1-immune complexes. , we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells.
CONCLUSIONS
-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Immunoglobulin A; Glomerular Mesangium; Complement Activation; Complement System Proteins
PubMed: 34615657
DOI: 10.2215/CJN.04300321