Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.
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ABSTRACT:
SUBMITTER: Zuckerman JE
PROVIDER: S-EPMC3286910 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In multicellular organisms, proteins of the extracellular matrix (ECM) play structural and functional roles in essentially all organs, so understanding ECM protein organization in health and disease remains an important goal. Here, we used sub-diffraction resolution stochastic optical reconstruction microscopy (STORM) to resolve the in situ molecular organization of proteins within the kidney glomerular basement membrane (GBM), an essential mediator of glomerular ultrafiltration. Using multichannel STORM and STORM-electron microscopy correlation, we constructed a molecular reference frame that revealed a laminar organization of ECM proteins within the GBM. Separate analyses of domains near the N- and C-termini of agrin, laminin, and collagen IV in mouse and human GBM revealed a highly oriented macromolecular organization. Our analysis also revealed disruptions in this GBM architecture in a mouse model of Alport syndrome. These results provide the first nanoscopic glimpse into the organization of a complex ECM. DOI:http://dx.doi.org/10.7554/eLife.01149.001.
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Project description:Atypical anti-glomerular basement membrane (anti-GBM) disease is characterized by linear immunoglobulin G (IgG) deposition along the GBM without circulating IgG anti-GBM antibodies. Compared to classic anti-GBM disease, atypical anti-GBM disease tends to be milder with a more indolent course in certain cases. Moreover, pathologic disease pattern is much more heterogenous in atypical anti-GBM disease than in the classic type, which is uniformly characterized by diffuse crescentic and necrotizing glomerulonephritis. Although there is no single well-established target antigen in atypical anti-GBM disease, the target antigen (within the GBM) and the autoantibody type are hypothesized to be different from the classic type. Some patients have the same antigen as the Goodpasture antigen that are detected only by a highly sensitive technique (biosensor analysis). Some cases of atypical anti-GBM disease have autoantibodies of a different subclass restriction like IgG4, or of monoclonal nature. Antibodies targeting antigen/epitope structure other than the Goodpasture antigen can be detected using modified assays in some cases. Patients with IgA- and IgM-mediated anti-GBM disease are known to have negative circulating antibodies because conventional assays do not detect these classes of antibodies. A significant proportion of cases with atypical anti-GBM disease do not have any identifiable antibodies despite extensive evaluation. Nevertheless, extensive evaluation of atypical autoantibodies using modified assays and sensitive techniques should be attempted, if feasible. This review summarizes the recent literature on atypical anti-GBM disease.
| S-EPMC10239794 | biostudies-literature
Project description:Estimates of levels of glomerular and glomerular-basement-membrane anion charge should serve as useful quantitative markers for the integrity of the tissues in health and disease. We have developed a simple, rapid, technique to measure this charge through the use of ion exchange with radioisotopes 22Na+ and 36Cl- at low ionic strengths in phosphate buffer. When this technique is used, normal glomeruli isolated from rat have a measured net anion charge concentration of 17.4 +/- 3.7 p-equiv. per glomerulus (n = 20). Perfused rat kidneys that lose approximately half of their glomerular heparan [35S]sulphate content (owing to oxygen-radical damage) exhibited a lower anion charge, of 7.5 +/- 1.6 p-equiv. per glomerulus (n = 5). Glomerular basement membranes prepared from rat glomeruli by a sonication-centrifugation procedure in the presence of enzyme inhibitors had a charge concentration of 6.3 +/- 0.7 mu-equiv./g wet wt. of tissue (n = 4), whereas membranes prepared by sonication, centrifugation, DNAse and detergent treatment had a charge concentration of 7.1 +/- 1.6 mu-equiv./g wet wt. (n = 4). Isotope-dilution experiments with 3H2O on these detergent-prepared glomerular basement membranes demonstrated that they had a water content of approx. 93%, which would then give a net anion charge concentration of 7.6 +/- 1.7 m-equiv./l (n = 4). These values are in good agreement with those obtained by others using titration techniques [Bray and Robinson (1984) Kidney Int. 25, 527-533]. The relatively low magnitude of glomerular anion charge in normal kidneys is consistent with other recent findings that glomerular anion charge is too low to affect the glomerular transport of charged molecules in a direct, passive, biophysical manner through electrostatic interactions.
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| S-EPMC6451084 | biostudies-literature
Project description:A 46-year-old female presented with a chief complaint of fatigue and intermittent painless gross hematuria for one month. The patient was fluid overloaded on physical examination and noted to be in acute renal failure with a serum creatinine of 10.8 mg/dL. The patient was emergently started on hemodialysis. Serologies were negative for antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibody (ANCA), and anti-glomerular basement membrane (anti-GBM) antibody. However, renal biopsy revealed 90% glomerular involvement by temporally heterogeneous crescents ranging from cellular to fibrous. Immunofluorescence studies revealed strong, linear glomerular capillary wall staining for immunoglobulin G (IgG). Although the patient was treated with pulse dose steroids and cyclophosphamide, the patient ultimately developed infectious complications from immunosuppression, and treatment was terminated. This case highlights the atypical presentation of anti-GBM disease diagnosed based on renal biopsy with negative serologies. Although rare, the possibility of atypical anti-GBM antibodies which are not detected by standard commercial assays should be considered in such cases.
| S-EPMC6603348 | biostudies-literature
Project description:BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
| S-EPMC6779358 | biostudies-literature
Project description:The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged and tracer studies showed delayed clearance of IgG from the kidneys of FcRn deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases. Keywords: Unique cell type expression analysis
2008-01-01 | GSE10017 | GEO
Project description:Anti-glomerular basement membrane (GBM) nephritis is characterized by circulating anti-GBM antibodies and crescentic glomerulonephritis (GN) with deposition of IgG along the GBM. In a limited number of cases, glomerular immune complexes have been identified in anti-GBM nephritis. A 38-year-old female presented azotemia, hematuria, and proteinuria without any pulmonary symptoms. A renal biopsy showed crescentic GN with linear IgG deposition along the GBM and mesangial IgA deposition. The patient was diagnosed as concurrent anti-GBM nephritis and IgA nephropathy. Therapies with pulse methylprednisolone and cyclophosphamide administration were effective. Concurrent cases of both anti-GBM nephritis and IgA nephropathy are rare among cases of anti-GBM diseases with deposition of immune complexes. This rare case of concurrent anti-GBM nephritis and IgA nephropathy with literature review is noteworthy.
| S-EPMC6877440 | biostudies-literature
Project description:1. After incubation of bovine glomeruli with D-[U-14C]glucose, about 21% of the total radioactivity is found in lipid extracts of glomerular basement membranes. 2. The concentration of lipids in glomerular basement membranes (4.3% of dry wt.) is lower than in the residual glomerular particles (10.8% of dry wt.). The concentrations of neutral lipids (13.9%), phospholipids (46.7%) and cholesterol (37.9%) in the total lipid extract of the glomerular basement membranes, however, differ from those in the residual glomerular particles (15.6, 54.0 and 30.9% respectively). Though residual glomerular particles show a higher lipid content, the radioactivity in this fraction only amounts to 38% of that found in the glomerular basement membranes. 3. The specific radioactivity of total glomerular basement-membrane lipids (12 600 d.p.m./mg) is about 4 times as high as that of the glomerular basement membranes. The specific radioactivities of the individual lipid components, however, differ. The highest values are found for phosphatidylcholine and triacylglycerols. The largest proportion of the radioactivity is found in the glycerol of the glycerides. The radioactivity in the fatty acids is much less and does not differ significantly in the various classes of lipids. 4. G.1.c. of methyl esters of the fatty acids does not reveal a clear difference between the fatty acid compositions of glomerular basement membranes and residual glomerular particles. 5. Treatment of glomerular basement-membrane preparations with ultrasound, the generally used procedure for glomerular basement-membrane preparations, drastically decreases the lipid content of glomerular basement membranes. 6. It is concluded that lipids are associated with the basement membranes. Further, the comparatively high radioactive labelling suggests that glomerular basement-membrane lipids may be an interesting class of substances for further pathological studies.
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Project description:Kidney physiology has diurnal variation and abnormal circadian rhythm is associated with kidney disease. However, it is not known whether glomeruli, the filtering units in the kidney, are under circadian control. We therefore investigated core circadian clock components in glomeruli, together with their rhythmic targets and modes of regulation.
2024-09-20 | E-MTAB-13457 | biostudies-arrayexpress