Minimal Change Diseas

Editor's Notes

• #3: MCNS: no changes under light microscopy. No signs of inflammation, immune complex deposition or schlerosis. FSGS: collapse of the glomerular capillaries with sclerosis and hyalinosis and the formation of adhesions of the glomerular tuft
• #4: recent genetic approaches to familial idiopathic nephrotic syndromes have been determining factors in elucidating several molecular aspects of focal glomerular sclerosis
• #5: 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 -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; , -catenin; , -catenin; Z, ZO-1; 3, 3-integrin; 1, 1−integrin; V, vinculin; T, talin; P, paxillin; -act-4, -actinin-4; synpo, synaptopodin. http://images.google.com/imgres?imgurl=http://www.nature.com/ng/journal/v24/n4/thumbs/ng0400_333_F3.gif&imgrefurl=http://www.nature.com/ng/journal/v24/n4/full/ng0400_333.html&h=84&w=150&sz=7&hl=en&start=1&tbnid=20SvGpeqTACs9M:&tbnh=54&tbnw=96&prev=/images%3Fq%3Dactinin%2Bpodocyte%26gbv%3D2%26svnum%3D10%26hl%3Den%26sa%3DG There’s been studies which show that nephrin may be involved in MCD but to date most genetic and animal models have shown FSGS
• #6: Clinical observations… -MCD frequently remits with measles infection (viral-associated immunosuppresion) -the therapeutic benefits of steroids and cyclophosphamide which abate cell-mediated responses -and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency 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. - ideal of glomerular permeability factor (GPF). - 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.
• #9: 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.
• #12: 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.
• #13: …. , because the glomerular expression of WT-1 and synaptopodin, which are specific cell surface markers of podocytes, showed no significant difference between the control rats and the IL-13–transfected rats
• #17: Innate Immune function reduced inflammatory response attenuate expression of adhesion molecules on endothelial and leukocytes (via inhibition of IL-1 and TNF) = thereby inhibiting transmigration of leukocytes Inhibiting generation of inflammatory exudates Suppressing 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 [9-12]. Suppressing 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 [13]. This effect primarily results from glucocorticoid suppression of NF-kB transcription. Glucocorticoids do not appear to affect the synthesis of constitutive cyclooxygenase-1 Inflammatory response: -attenuate expression of adhesion molecules on endothelial and leukocytes -attenuate the generation of inflammatory exudates
• #26: Study of dexamethasone on FSGS but can be translated to MCD?
• #27: 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 (Figure 2). 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 2a, no dexamethasone, Figure 2b, cells incubated with 10-5 M, Figure 2c 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 2d, 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 2e). Reverse transcriptase-polymerase chain reaction (RT-PCR) suggested that this effect was at least partly at the RNA level (Figure 2f, representative of five replicate experiments). Expression of other key podocyte proteins, including podocin,5CD2-associated protein,7 and synaptopodin10 was unaffected by dexamethasone (data not shown).
• #29: 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 repair VEGF, a mitogen for vascular endotheila cells downregulated Upregulated in MCD