A new mouse model of immune-mediated podocyte injury (original) (raw)
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Inducible rodent models of acquired podocyte diseases
Ajp: Renal Physiology, 2008
Running title: experimental podocyte injury models Abbreviations: ADR adriamycin; SD Sprague-Dawley; IV intravenous; IP intraperitoneal; SQ subcutaneous; FSGS focal segmental glomerulosclerosis; GBM glomerular basement membrane; MCD minimal change disease; PA puromycin aminonucleoside; PAN puromycin aminonucleoside nephrosis; PHN passive Heymann nephritis; GN glomerulonephritis; PS protamine sulfate (PS); LPS Lipopolysaccharide ABSTRACT Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired non-diabetic podocyte diseases in rodents namely: passive Heyman nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis , liopolysaccharide, crescentic glomerulonephritis and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded. Experimental podocyte disease models J.W. Pippin et al. tional activation (97,73,54,103). Podocytes are vulnerable to many forms of injury. Immune-mediated processes include immune complex deposition with subsequent complement activation, as seen in membranous nephropathy (125), as well as cellular mechanisms characteristic of minimal change disease or focal segmental glomerulosclerosis (FSGS) (109). Non-immune injury includes Experimental podocyte disease models J.W. Pippin et al. 4
The American Journal of Pathology, 2006
Changes in podocyte number or density have been suggested to play an important role in renal disease progression. Here , we investigated the temporal relationship between glomerular podocyte number and development of proteinuria and glomerulosclerosis in the male Munich Wistar Fromter (MWF) rat. We also assessed whether changes in podocyte number affect podocyte function and focused specifically on the slit diaphragm-associated protein nephrin. Age-matched Wistar rats were used as controls. Estimation of podocyte number per glomerulus was determined by digital morphometry of WT1positive cells. MWF rats developed moderate hypertension , massive proteinuria , and glomerulosclerosis with age. Glomerular hypertrophy was already observed at 10 weeks of age and progressively increased thereafter. By contrast , mean podocyte number per glomerulus was lower than normal in young animals and further decreased with time. As a consequence , the capillary tuft volume per podocyte was more than threefold increased in older rats. Electron microscopy showed important changes in podocyte structure of MWF rats , with expansion of podocyte bodies surrounding glomerular filtration membrane. Glomerular nephrin expression was markedly altered in MWF rats and inversely correlated with both podocyte loss and Supported in part by the Commission of the European Communities within the EuReGene project (LSHG-CT-2004-005085).
Podocyte Antigens and Glomerular Disease
Nephron Experimental Nephrology, 2007
Background: Membranous nephropathy (MN), a major cause of nephrotic syndrome in the adult, is an immune-mediated disease characterized by the accumulation of subepithelial immune deposits leading to complement activation and podocyte injury. However, the target antigens of circulating antibodies are unknown. Current treatments for patients with MN are entirely empirical, and concept-driven therapies are dramatically lacking. Methods: Specificity of circulating antibodies and composition of glomerular deposits were analyzed in Heymann nephritis (HN), a faithful rat model of MN, and in a subset of patients with antenatal MN. Results: 20 years after the identification of megalin as the podocyte target antigen of nephritogenic antibodies in HN, we identified the human counterpart of megalin, the enzymatic podocyte antigen neutral endopeptidase (NEP). Antibodies to megalin or NEP induce formation of subepithelial immune deposits and of C5b-9, the membrane attack complex of complement. Co...
Role of Podocyte in Kidney Disease
Podocytes are epithelial cells lining the outer surface of the renal glomerular capillaries and they play a pivotal role in maintaining the structural and functional integrity of the glomerular filtration barrier. Podocytes react to injury in various ways and any injury to these highly specialized cells can progress to podocyte dysfunction, resulting in a group of proteinuric renal diseases called podocytopathies. Podocytopathies include a wide spectrum of primary and secondary kidney diseases, including minimal change disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis, collapsing glomerulopathy, diabetic, membranous and lupus nephropathies. Etiologically, they can be idiopathic, genetic or secondary to infections and drugs, metabolic diseases, hemodynamic factors or associated with various immune and non-immune systemic diseases. This manuscript provides a basic understanding of podocyte structure, causes of podocyte injury, response to the injury and the subsequent progression to podocytopathies. The pathogenesis of these diseases is set around podocytes. The clinical and morphological manifestations, the commonality and heterogeneity of these podocytopathies are also discussed. As our knowledge of podocyte biology improves, so will our treatment avenues with a more podocyte-centric personalized approach.
Podocytes Populate Cellular Crescents in a Murine Model of Inflammatory Glomerulonephritis
Journal of the American Society of Nephrology, 2004
Cellular crescents are a defining histologic finding in many forms of inflammatory glomerulonephritis. Despite numerous studies, the origin of glomerular crescents remains unresolved. A genetic cell lineage-mapping study with a novel transgenic mouse model was performed to investigate whether visceral glomerular epithelial cells, termed podocytes, are precursors of cells that populate cellular crescents. The podocytespecific 2.5P-Cre mouse line was crossed with the ROSA26 reporter line, resulting in irreversible constitutive expression of -galactosidase in doubly transgenic 2.5P-Cre/ROSA26 mice. In these mice, crescentic glomerulonephritis was induced with a previously described rabbit anti-glomerular basement membrane antiserum nephritis approach. Interestingly, -galactosi-dase-positive cells derived from podocytes adhered to the parietal basement membrane and populated glomerular crescents during the early phases of cellular crescent formation, accounting for at least one-fourth of the total cell mass. In cellular crescents, the proliferation marker Ki-67 was expressed in -galactosidase-positive and -galactosidase-negative cells, indicating that both cell types contributed to the formation of cellular crescents through proliferation in situ. Podocyte-specific antigens, including WT-1, synaptopodin, nephrin, and podocin, were not expressed by any cells in glomerular crescents, suggesting that podocytes underwent profound phenotypic changes in this nephritis model.
The glomerulus – a view from the outside – the podocyte
The International Journal of Biochemistry & Cell Biology, 2010
In the past decade, podocyte research has been greatly aided by the development of powerful new molecular, cellular and animal tools, leading to elucidation of an increasing number of proteins involved in podocyte function and identification of mutated genes in hereditary glomerulopathies. Accumulating evidence indicates that podocyte disorders may not only underlie these hereditary glomerulopathies but also play crucial role in a broad spectrum of acquired glomerular diseases. Genetic susceptibility, environmental influence and systemic responses are all involved in the mediation of the pathogenesis of podocytopathies. Injured podocytes may predisopose to further injury of other podocytes and other adjacent/distant renal cells in a vicious cycle, leading to inexorable progression of glomerular injury. The classic view is that podocytes have a limited ability to proliferate in the normal mature kidney. However, recent research in rodents has provided suggestive evidence for podocyte regeneration resulting from differentiation of progenitor cells within Bowman's capsule.
Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy
Nephrology Dialysis …, 2009
Background. We have previously documented that human mesangial cell (HMC)-derived tumour necrosis factor-α (TNF-α) is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the function of podocytes in IgAN. Methods. Podocyte markers were examined in renal tissues by immunofluorescence. In vitro experiments were conducted with podocytes cultured with polymeric IgA (pIgA) or conditioned medium prepared from HMC incubated with pIgA (IgA-HMC conditioned medium). Results. Glomerular immunostaining for nephrin or ezrin was significantly weaker in patients with IgAN. The immunostaining of IgA and nephrin was distinctly separate with no co-localization. In vitro experiments revealed no effect of pIgA on the expression of these podocyte proteins as IgA from IgAN patients did not bind to podocytes. In contrast, IgA conditioned medium prepared from IgAN patients down-regulated the expression of these podocyte proteins as well as other podocyte markers (podocin and synaptopodin) in cultured podocytes. The mRNA expression of nephrin, erzin, podocin but not synaptopodin correlated with the degree of proteinuria and creatinine clearance. The down-regulation was reproducible in podocytes cultured with TNF-α or transforming growth factor-β (TGF-β) at concentration comparable to that in the IgA-HMC conditioned medium. The expression of these podocyte proteins was restored partially with a neutralizing antibody against TNF-α or TGF-β and fully with combination of both antibodies. Conclusion. Our finding suggests podocyte markers are reduced in IgAN. An in vitro study implicates that humoral factors (predominantly TNF-α and TGF-β) released from mesangial cells are likely to alter the glomerular permeabil
The Interaction of Podocytes, Glomerular Cells and Mesangial Cells in Glomerulopathies
American Journal of Biomedical Science & Research, 2021
Compared to primary glomerulopathies, secondary glomerulopathies refer to those in which glomerular damage is part of a complex clinical picture, caused by different processes: immunological, tumors, hereditary, infections or drugs, the classic examples are triggered by the systemic lupus erythematosus (SLE), diabetes, among others See Tables 1&2 [4]. During years, glomerulopathies have been closely related to chronic kidney disease (CKD) [5], occupying the first places of CKD triggers according to the 2017 report of the "The United States Renal Data Am J Biomed Sci & Res