Pathogenesis of minimal change nephrotic syndrome: an immunological concept / 소아과

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia. Minimal change nephrotic syndrome (MCNS) is the most common form of INS in children. The pathogenesis of MCNS still remains unclear, however, several hypotheses have been recently proposed. For several decades, MCNS has been considered a T-cell disorder, which causes the impairment of the glomerular filtration barrier with the release of different circulating factors. Increased levels of several cytokines are also suggested. Recently, a "two-hit" theory was proposed that included the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory functions of the podocyte. In contrast to the well-established involvement of T cells, the role of B cells has not been clearly identified. However, B-cell biology has recently gained more attention, because rituximab (a monoclonal antibody directed against CD20-bearing cells) demonstrated a very good therapeutic response in the treatment of childhood and adult MCNS. Here, we discuss recent insights into the pathogenesis of MCNS in children.

Effects of Interleukin-13 and Montelukast on the Expression of Zonula Occludens-1 in Human Podocytes

PURPOSE: The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. MATERIALS AND METHODS: Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. RESULTS: ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 microM) montelukast treatment (p<0.01; n=3). CONCLUSION: Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.

Effects of Interleukin-13 and Montelukast on the Expression of Zonula Occludens-1 in Human Podocytes

PURPOSE: The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. MATERIALS AND METHODS: Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. RESULTS: ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 microM) montelukast treatment (p<0.01; n=3). CONCLUSION: Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.

Current concepts of the podocyte in nephrotic syndrome

Nephrotic syndrome is a disorder of the glomerular filtration barrier, and central to the filtration mechanism of the glomerular filtration barrier is the podocyte. We are starting to better understand how this cell, with its unique architectural features, fulfils its exact filtration properties. The multiprotein complex between adjacent podocyte foot processes, the slit diaphragm, is essential to the control of the actin cytoskeleton and cell morphology. Many of the proteins within the slit diaphragm, including nephrin, podocin, transient receptor potential-6 channel, and alpha-actinin-4, have been identified via genetic studies of inherited nephrotic syndromes. Signaling from slit diaphragm proteins to the actin cytoskeleton is mediated via the Rho GTPases. These are thought to be involved in the control of podocyte motility, which has been postulated as a focus of proteinuric pathways. Nephrotic syndrome is currently treated with immunosuppressive therapy, with significant adverse effects. These therapies may work in nephrotic syndrome due to specific effects on the podocytes. This review aims to describe our current understanding of the cellular pathways and molecules within the podocyte relevant to nephrotic syndrome and its treatment. With our current knowledge of the cellular biology of the podocyte, there is much hope for targeted therapies for nephrotic syndromes.