Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Berre, Ludmilla Le; Godfrin, Yann; Günther, Eberhard; Buzelin, F; Perretto, Sabine; Smit, Helga; Kerjaschki, Dontscho; Usal, Claire; Cuturi, Cristina; Soulillou, Jean‐Paul; Dantal, Jacques

doi:10.1172/jci12858

Cited by 29 publications

(13 citation statements)

References 41 publications

(18 reference statements)

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“…However, it has been reported that proteinuria in two FSGS kidneys disappeared after transplantation in two recipients [69]. Likewise, in a rat model of FSGS, the spontaneously proteinuric Buffalo/Mna rat model, disease recurs in the donor kidney from healthy control rats transplanted into Buffalo/Mna recipients and proteinuria and renal lesions regress when the Buffalo/Mna kidneys are transplanted into normal control rats [70]. These data suggest that the FSGS kidney does not bear the causative defect.…”

Section: Circulating Permeability Factorsmentioning

confidence: 94%

Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

2004

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Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in the glomerular barrier to proteins. Genetic defects that affect the function and the composition of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been recognized as the cause of familial forms of NS. MCNS (minimal change NS) and FSGS (focal and segmental glomerulosclerosis) are common non-familial forms of NS in which the causative defect has not yet been identified. Several studies have shown that non-familial NS is associated with the presence of circulating permeability factors and with complex disturbances in the immune system. Thus far, there is no direct evidence that these factors directly alter glomerular permeability to proteins, and some of these factors may be a consequence, rather than a cause, of NS. In this review, we will briefly highlight the mechanisms that underlie proteinuria in general and focus on the immunological disturbances associated with idiopathic NS, with attention to potential mechanisms whereby the immune system may directly act on the glomerular capillary filter.

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Section: Circulating Permeability Factorsmentioning

confidence: 94%

Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

2004

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“…Abnormal signaling-induced assembly of actin in podocytes leads to the development of FSGS [28]. The slower progression of the disease also mimics the slower development in human disease [29,30]. Nevertheless, the slower pace of deterioration also brings disadvantages for practical research use (Table 1).…”

Section: Buffalo/mwf Modelmentioning

confidence: 99%

Recent advances of animal model of focal segmental glomerulosclerosis

Yang

Dettmar

Kronbichler³

et al. 2018

Clin Exp Nephrol

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In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models. Classic animal models of FSGS involve direct podocyte injury and indirect podocyte injury due to adaptive responses. However, the phenotype depends on the animal background. Renal ablation and direct podocyte toxin (PAN, adriamycin) models are leading animal models for FSGS, which have some limitations depending on mice background. A second group of animal models were developed using combinations of genetic mutation and toxin, such as NEP25, diphtheria toxin, and Thy1.1 models, which specifically injure podocytes. A third group of animal models involves genetic engineering techniques targeting podocyte expression molecules, such as podocin, CD2-associated protein, and TRPC6 channels. More detailed information about podocytopathy and FSGS can be expected in the coming decade. Different animal models should be used to study FSGS depending on the specific aim and sometimes should be used in combination.

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“…There is also evidence, in FSGS and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. 71,72 The role of podocytes in the progression of glomerular diseases From the viewpoint of progressive glomerular disease, it is important to recognize that if the early structural changes are not reversed, severe and progressive glomerular damage develops. This involves: (a) cell-body attenuation; (b) pseudocyst formation and vacuolization; (c) detachment from the GBM, resulting in podocyte depletion; (d) cell hypertrophy, but no cell proliferation and also cell death; and (e) the formation of synechiae by the attachment of parietal epithelial cells to denuded GBM.…”

Section: Major Causes Of Podocyte Injurymentioning

confidence: 99%

The role of podocytes in glomerular pathobiology

Asanuma

Mündel

2003

Clinical and Experimental Nephrology

229

198

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Podocytes are unique cells with a complex cellular organization. With respect to their cytoarchitecture, podocytes may be divided into three structurally and functionally different segments: cell body, major processes, and foot processes (FPs). The FPs of neighboring podocytes regularly interdigitate, leaving between them the filtration slits that are bridged by an extracellular structure, known as the slit diaphragm (SD). Podocytes cover the outer aspect of the glomerular basement membrane (GBM). They therefore form the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Chronic podocyte injury may lead to podocyte detachment from the GBM. Our knowledge of the molecular structure of the SD has been remarkably improved in the past few years. Several molecules, including nephrin, CD2AP, FAT, ZO-1, P-cadherin, Podocin, and Neph 1-3 have all been shown to be associated with the SD complex, and some of these molecules are critical for its integrity. Podocytes are injured in many forms of human and experimental glomerular disease. The early events are characterized either by alterations in the molecular composition of the SD without visible changes in morphology or, more obviously, by a reorganization of FP structure with the fusion of filtration slits and the apical displacement of the SD. Based on recent insights into the molecular pathology of podocyte injury, at least four major causes have been identified that lead to the uniform reaction of FP effacement and proteinuria: (1) interference with the SD complex and its lipid rafts; (2) direct interference with the actin cytoskeleton; (3) interference with the GBM or with podocyte-GBM interaction; and (4) interference with the negative surface charge of podocytes. There is also evidence, in focal segmental glomerular sclerosis (FSGS) and in idiopathic nephrotic syndrome in humans and rats, that podocyte damage may be caused by circulating albuminuric factors. Ongoing studies in many laboratories are aiming at an understanding of the dynamic relationship between SD proteins, the actin cytoskeleton, and the dynamics of FP structure in nephrotic syndrome and FSGS. These studies should provide us with a better understanding of the biological mechanism underlying the podocyte response to injury. Such studies will potentially translate into more refined treatment and the prevention of proteinuria and progressive glomerular disease.

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Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Cited by 29 publications

References 41 publications

Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome

Recent advances of animal model of focal segmental glomerulosclerosis

The role of podocytes in glomerular pathobiology

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