MCNS: no changes under light microscopy. No signs of inflammation, immune complex deposition or sclerosis. FSGS: collapse of the glomerular capillaries with sclerosis and hyalinosis and the formation of adhesions of the glomerular tuft|~|/files/powerpoints_images/node391142/Slide3.JPG|~|563|~|422|~|0
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MCNS: no changes under light microscopy. No signs of inflammation, i...
MCD has no glomerular lesions by light microscopy. The thickness of the glomerular capillary walls is normal, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes and there is neither expansion nor hypercellularity in the mesangial areas in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke.|~|/files/powerpoints_images/node391142/Slide4.JPG|~|563|~|422|~|0
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MCD has no glomerular lesions by light microscopy. The thickness of t...
Shows no staining with antisera specific for IgG, IgA, IgM, C3, C4, or C1q. Absence of humoral components of the immune system. There are occasional specimens that will have small amounts of exclusively mesangial immunoglobulin (especially IgM) or complement accumulation that can still be designated minimal change glomerulopathy. A little bit of mesangial IgM and/or C3 without ultrastructural evidence for electron dense deposits is tolerable for a diagnosis of minimal change glomerulopathy. Well defined mesangial electron dense deposits, however, worsen the prognosis for response to steroids or spontaneous remission. Thus, if there are electron dense deposits, minimal change glomerulopathy is not an appropriate diagnoses.|~|/files/powerpoints_images/node391142/Slide5.JPG|~|563|~|422|~|0
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Shows no staining with antisera specific for IgG, IgA, IgM, C3, C4, o...
Characteristic histologic finding in MCD is diffuse effacement of the epithelial ceel foot proces on EM. A finding also observed with FGS. Electron micrograph in minimal change disease showing a normal glomerular basement membrane (GBM), no immune deposits, and the characteristic widespread fusion of the epithelial cell foot processes (arrows). Courtesy of Helmut Rennke, MD.|~|/files/powerpoints_images/node391142/Slide6.JPG|~|563|~|422|~|0
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Characteristic histologic finding in MCD is diffuse effacement of the...
Cross-sections of the glomerular capillary wall in a non-proteinuric patient (A and B) and in a patient with MCNS (C and D) as revealed by electron microscopy. cell bodies of podocytes (P) extend into the urinary space, while their foot processes attach to the GBM. In normal individuals, foot processes are arranged in a regular interdigitating pattern (B) with interconnecting slit diaphragms (small arrows). In nephrotic patients, foot processes are irregularly flattened and show distorted slit diaphragms (D; arrowhead). US, urinary space; CL, capillary lumen. Magnification, ×11 000 (A and C) and ×108 000 (B and D).|~|/files/powerpoints_images/node391142/Slide7.JPG|~|563|~|422|~|0
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Cross-sections of the glomerular capillary wall in a non-proteinuric ...
Recent genetic approaches to familial idiopathic nephrotic syndromes have been determining factors in elucidating several molecular aspects of focal glomerular sclerosis. |~|/files/powerpoints_images/node391142/Slide9.JPG|~|563|~|422|~|0
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Recent genetic approaches to familial idiopathic nephrotic syndromes ...
These proteins include molecules that locate at the slit diaphragm (nephrin, neph1, podocin, CD2AP and the Src family kinase Fyn), transcription factors (WT-1, Lmx1B, Pod1 and Krml1/MafB), cytoskeletal components (α-actinin-4 and RhoGDIα), adhesion molecules (α3 integrin) and components of the GBM (S-laminin/laminin β2). (1) a contractile system composed of actin, myosin-II, -actinin-4, talin, vinculin and synaptopodin that is connected to the GBM via 31 integrin. (2). The linkage of the actin cytoskeleton to the slit diaphragm components, nephrin and P-cadherin, may be mediated by CD2AP or by a complex of ZO-1, and different types of catenin. (3) The localization of podocin in the podocyte cell membrane remains to be established. The actin cytoskeleton is well suited to integrate different signalling pathways from the matrix:GBM interface, the slit diaphragm or the cell surface. Disruption of any of these pathways may lead to reorganization of the actin cytoskeleton and foot process effacement as seen with nephrotic syndrome. N, nephrin; P-C, P-cadherin; , catenin; Z, ZO-1; 3, 3-integrin; 1, 1−integrin; V, vinculin; T, talin; P, paxillin; -act-4, -actinin-4; synpo, synaptopodin. There’s been studies which show that nephrin may be involved in MCD but to date most genetic and animal models have shown FSGS. http://images.google.com/imgres?imgurl=http://www.nature.com/ng/journal/v24/n4/thumbs/ng0400_333_F3.gif|~|/files/powerpoints_images/node391142/Slide10.JPG|~|563|~|422|~|0
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These proteins include molecules that locate at the slit diaphragm (n...
CLINICAL OBSERVATIONS: Three lines of data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease. (1) MCD frequently remits with measles infection (viral-associated immunosuppresion). (2) Steroids and cyclophosphamide abate cell-mediated responses and have benefical therapeutic effects. (3) This syndrome occurs in Hodgkin\'s disease. EXPERIMENTAL OBSERVATIONS: Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. In study by Koyama, where T cell hybridomas was derived from the T cells of a patient with MCD, and injection of supernatants from the T-cell hybridoma from patients in relapse into rats caused immediate proteinuria and glomerular podocyte foot process fusion, where as no changes were ntoed when the T-cell hybridoma supernatants from healthy controls was fused. (i) ideal of glomerular permeability factor (GPF). (ii) The molecular weight of the factor and its TNF like activity, we speculated that the factor was a lymphokine, like lymphotoxins. This is supported by intriguing observation that transplantation of a kidney from a patient with refractory MCD resulted in rapid disappearance of proteinuria in the recipients.|~|/files/powerpoints_images/node391142/Slide11.JPG|~|563|~|422|~|0
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CLINICAL OBSERVATIONS: Three lines of data suggest that this syndrome...
EFFECTS ON INNATE IMMUNITY: reduced inflammatory response; attenuate expression of adhesion molecules on endothelial and leukocytes (via inhibition of IL-1 and TNF) = thereby inhibiting transmigration of leukocytes; Inhibit generation of inflammatory exudates; Suppress production of inflammatory eicosanoids in phagocytic cells by inducing the synthesis of lipocortin-1 (annexin I), macrocortin, and/or lipomodulin, all of which inhibit phospholipase A2 (PLA2)-mediated liberation of arachidonic acid from membrane phospholipids; Suppress the synthesis of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase primarily responsible for production of prostaglandins at sites of tissue injury and inflammation. This effect primarily results from glucocorticoid suppression of NF-kB transcription. Glucocorticoids do not appear to affect the synthesis of constitutive cyclooxygenase-1. EFFECTS ON INFLAMMATORY RESPONSE: Attenuate expression of adhesion molecules on endothelial and leukocytes; Attenuate the generation of inflammatory exudates.|~|/files/powerpoints_images/node391142/Slide13.JPG|~|563|~|422|~|0
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EFFECTS ON INNATE IMMUNITY: reduced inflammatory response; attenuate ...
Molecular mechanisms of neurotransmitter and glucocorticoid regulation of cytokine production: Glucocorticoids bind to glucocorticoid receptors in the cytosol, which displaces heat-shock protein 90 (HSP90) and allows receptor dimerization, movement into the nucleus and binding of the glucocorticoid–glucocorticoid-receptor complex to DNA. This leads to transcription and translation of proteins, including inhibitor of nuclear factor-B (IB). IB then sequesters NF-B, preventing it from activating transcription of pro-inflammatory cytokines. In addition, the glucocorticoid–glucocorticoid-receptor complex can interact with NF-B directly to suppress cytokine production. |~|/files/powerpoints_images/node391142/Slide14.JPG|~|563|~|422|~|0
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Molecular mechanisms of neurotransmitter and glucocorticoid regulatio...
Study of dexamethasone on FSGS but can be translated to MCD.|~|/files/powerpoints_images/node391142/Slide16.JPG|~|563|~|422|~|0
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Study of dexamethasone on FSGS but can be translated to MCD.
We found that dexamethasone enhanced and accelerated podocyte maturation, with a particularly striking effect on expression of nephrin. Nephrin expression was upregulated after 14 days incubation with dexamethasone. Immunofluorescent staining is not regarded as a quantitative technique, but there is a striking difference in the amount of fluorescence seen in images taken on identical exposure settings with anti-nephrin rabbit polyclonal antibody K2966 according to the presence or absence of dexamethasone in the culture medium for 14 days (Figure a, no dexamethasone, Figure b, cells incubated with 10-5 M, Figure c negative control immunofluorescence with rabbit immunoglobulin (Ig) for comparison). Quantitation by Western blot with rabbit polyclonal anti-nephrin antibody K2737 confirmed dose-dependent upregulation of nephrin protein by dexamethasone (Figure d, representative of five replicate experiments). Nephrin is a large-molecular-weight membrane-bound protein and is known to be difficult to blot, accounting for the indistinct bands. We therefore show detailed densitometric quantification of three replicate Western blots, which showed nephrin/actin ratios of 1.0:1.33:1.618 with 0, 10-7, and 10-5 M dexamethasone, respectively (P<0.05, Figure e). |~|/files/powerpoints_images/node391142/Slide17.JPG|~|563|~|422|~|0
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We found that dexamethasone enhanced and accelerated podocyte maturat...
OTHER EFFECTS OF STEROIDS: Podocytes’s capacity for replication; Role of p21: Upregulated in diseases characterized by podocyte injury; Enhanced podocyte survival; p21 downregulation allow podocyte to enter the cell cycle – enhance ability to repairVEGF, a mitogen for vascular endotheila cells downregulatedUpregulated in MCD.|~|/files/powerpoints_images/node391142/Slide19.JPG|~|563|~|422|~|0
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OTHER EFFECTS OF STEROIDS: Podocytes’s capacity for replication; Ro...
Mean 24-h urine albumin excretion (mg/24 h) of control rats (n = 17) and IL-13–transfected rats (n = 41) measured at 14-d intervals. Data are means ± SEM.|~|/files/powerpoints_images/node391142/Slide22.JPG|~|563|~|422|~|0
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Mean 24-h urine albumin excretion (mg/24 h) of control rats (n = 17) ...
Immunofluorescence examination showed that nephrin, podocin, and dystroglycan all stained strongly as a continuous granular pattern along the GBM in the control rats. This was in contrast to the nephrotic rats, in which the fluorescence signal was much weaker and in a discontinuous, and sometimes segmental, granular pattern along the GBM. Of note, there was no significant difference between the control and nephrotic rats in the expression of synaptopodin, which showed strong and continuous staining along the GBM. In FSGS usually podocytopenia results where there’s decrease in the number of podocyte 2/2 stress, injury, intrinsic factor. IN MCD, there’s a phenotypic change with decrease in absolute no of podocyte.|~|/files/powerpoints_images/node391142/Slide25.JPG|~|563|~|422|~|0
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Immunofluorescence examination showed that nephrin, podocin, and dyst...
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