Proteinuria and Fusion of Podocyte Foot Processes in Rats after Infusion of Cytokine from Patients with Idiopathic Minimal Lesion Nephrotic Syndrome

Garin, Eduardo H.; Laflam, Paul; Muffly, Karl E.

doi:10.1159/000089689

Cited by 12 publications

(8 citation statements)

References 70 publications

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“…PBMC were isolated by density centrifugation on a Ficoll-Hypaque gradient as previously described [11] and cultured in 5 ml of RPMI (Grand Island Biological, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (FBS) in Petri dishes for 72 h at 35°C, at a concentration of 1×10 6 cells/ml [4]. At the end of the incubation time supernatants were collected and concentrated 1.5- to 9-fold.…”

Section: Methodsmentioning

confidence: 99%

“…Injection into rats of supernatants from the T-cell hybridoma from patients in relapse caused immediate proteinuria and glomerular podocyte foot process fusion, whereas no changes were noted when the T-cell hybridoma supernatants from healthy controls were infused [3]. Proteinuria has also been reported when supernatants from cultures of peripheral blood mononuclear cells (PBMC) from MCD patients in relapse were infused into rats [4]. However, despite numerous efforts over the last 30 years, the pathogenic cytokine has not been identified and the mechanism of proteinuria in these patients has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes

et al. 2013

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Background Minimal Change Disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes with increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes. Methods Sera and peripheral blood mononuclear cells were collected from subjects with MCD in relapse and remission, and normal controls. Immortalized human podocytes were incubated with culture media containing patient sera or supernatants from patient and control peripheral blood mononuclear cell (PBMC) cultures. CD80 expression was measured by quantitative PCR and western blot analysis. Results Sera from MCD in relapse, but not in remission, significantly increased CD80 expression (1.8±0.7 vs 0.8±0.2) (mean±SD) (p<0.004) and CD80 protein secretion by podocytes (p<0.05 between relapse and normal controls). No such CD80 increase was observed when podocytes were incubated with supernatants of PBMC cultures from patients in relapse. Conclusions MCD sera from patients in relapse, but not in remission, stimulates CD80 expression in cultured podocytes. Identifying this factor in sera could provide insights into the pathogenesis of this disorder. No role in CD80 expression by podocytes was found for cytokines released by PBMCs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes

et al. 2013

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“…A specific pathogenic cytokine has not yet been identified, but several cytokines known to be elevated in the serum of patients with IMLNS during relapse have been shown to increase glomerular permeability to plasma proteins, among them interleukin (IL)-8 [3], 100 kDa glycoprotein [4], IL-13 [5], and a cytokine described by Koyama et al [6]. These latter authors were able to immortalize T cells from patients with IMLNS and show that the T cell culture supernatants could induce massive proteinuria in rats.…”

Section: Introductionmentioning

confidence: 99%

T regulatory cell function in idiopathic minimal lesion nephrotic syndrome

et al. 2009

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The purpose of this study was to test the hypothesis that, in idiopathic minimal lesion nephrotic syndrome (IMLNS), the T regulatory (T reg) cell suppressor mechanism is deficient, thereby enhancing cytokine release by T effector cells. Twenty-one patients with IMLNS, eight healthy controls and two patients with nephrotic syndrome and membranoproliferative glomerulonephritis were studied. The percentage of T reg cells was similar in the healthy controls and in patients with IMLNS in relapse or in remission. Thymidine incorporation in autologous T effector cells, as well as expression of the regulatory cytokine interleukin (IL)-10, was significantly reduced in patients in relapse when compared with patients in remission and healthy subjects. IL-2 expression was also reduced in patients in relapse but did not achieve statistical significance. In a different set of experiments, T cells, from subjects with IMLNS in remission, when stimulated with antiCD3-antiCD28 antibodies, secreted increased levels of cytokines. No such increase in cytokines was observed when cells from healthy controls were stimulated with same mitogen. The impaired T reg cell function observed in these patients may have pathogenic and therapeutic implications, because it could explain the persistence of the proposed pathogenic cytokines observed in the patients with IMLNS.

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“…Therefore, whether our conclusion can be generalized to other MCD animal models like lipopolysaccharide-induced MCD as well as human MCD is questionable [25]. For instance, some investigators using clinical observation argued that there was no causal relationship between foot process effacement and proteinuria [26, 27], though most preclinical studies on MCD showed that the 2 factors were associated with each other [9, 28, 29]. The success of calcineurin inhibitors such as cyclosporine A and FK506 in clinical practice suggested that the activation of calcineurin in human MCD patients may be true and thus showed a bright future [21].…”

Section: Discussionmentioning

confidence: 99%

miR-499 Ameliorates Podocyte Injury by Targeting Calcineurin in Minimal Change Disease

Zhang¹,

Sun²,

Zhang³

et al. 2018

Am J Nephrol

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Background: Podocyte injury is a hallmark of minimal change disease (MCD). Calcineurin inhibitors have been widely used in the current treatment of MCD, and miR-499 may target calcineurin. We aimed to study the function of miR-499 in MCD and test whether miR-499 delivery can improve MCD. Methods: An MCD mouse model was generated using puromycin aminonucleoside (PAN). MiR-499 was delivered using lentiviruses. Biochemical indicators including serum albumin, triglyceride, cholesterol, and 24-h urine protein were determined. Targets of miR-499 were confirmed using reporter gene activity assays. The ultrastructure of podocytes was analyzed using transmission electron microscopy. Results: MiR-499 significantly improved MCD-related symptoms and signs. Foot-process effacement was caused by PAN and partially reversed by miR-499. We identified that both CnAα and CnAβ were targets of miR-499, and were overexpressed in the presence of PAN. However, miR-499 reduced the expression of CnAα and CnAβ, leading to a decreased activity of calcineurin signaling in mouse podocytes in vitro and in vivo. In addition, miR-499 recovered PAN-induced reduction of cell viability. Conclusions: MiR-499 ameliorated podocyte injury by targeting CnAα and CnAβ in a PAN-induced MCD mouse model. Delivery of miR-499 can be a novel strategy for MCD treatment.

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Proteinuria and Fusion of Podocyte Foot Processes in Rats after Infusion of Cytokine from Patients with Idiopathic Minimal Lesion Nephrotic Syndrome

Cited by 12 publications

References 70 publications

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes

T regulatory cell function in idiopathic minimal lesion nephrotic syndrome

miR-499 Ameliorates Podocyte Injury by Targeting Calcineurin in Minimal Change Disease

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