Genetic kidney diseases disclose the pathogenesis of proteinuria

Jalanko, Hannu; Patrakka, Jaakko; Tryggvason, Karl; Holmberg, Christer

doi:10.3109/07853890108995962

Cited by 32 publications

(20 citation statements)

References 62 publications

(21 reference statements)

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“…Nephrin is a podocyte protein that has a crucial role in ultrafiltration of plasma in kidney glomerulus (2,28). Mutations in the nephrin gene lead to congenital nephrotic syndrome, and the protein may also play a role in acquired kidney diseases (29,30).…”

Section: Discussionmentioning

confidence: 99%

Tissue Expression of Nephrin in Human and Pig

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Tissue Expression of Nephrin in Human and Pig

et al. 2004

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“…Nephrin is a member of the immunoglobulin (Ig) superfamily characterized by eight C2 type Ig-like domains and a fibronectin type III repeat in its extracellular region. For this reason, it has been proposed that Nephrin is a cell adhesion molecule (CAM) 1 that participates in forming the glomerular filter via homophilic or heterophilic interactions involving its extracellular domain (9,10). However, the Nephrin ligand has not been identified.…”

mentioning

confidence: 99%

Nephrin and Neph1 Co-localize at the Podocyte Foot Process Intercellular Junction and Form cis Hetero-oligomers

Barletta

Kovari

Verma

et al. 2003

Journal of Biological Chemistry

170

147

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Glomerular visceral epithelial cells (podocytes) appear to play a central role in maintaining the selective filtration barrier of the renal glomerulus. While the immunoglobulin superfamily member Nephrin was proposed to act as a cell adhesion molecule at the podocyte intercellular junction necessary for maintaining glomerular perm selectivity, the Nephrin ligand has not been identified. The existence of a new subfamily of Nephrin-like molecules including Neph1 was recently described. Genetic deletion of Nephrin or Neph1 resulted in similar phenotypes of podocyte foot process effacement and proteinuria. The subcellular localization of Neph1 and the possibility that Nephrin and Neph1 interact was investigated. Polyclonal antiserum for Neph1 was raised and characterized. Neph1 migrated as a 90-kDa protein on SDS-PAGE under reducing conditions. Neph1 was identified in a glomerular and podocyte-specific distribution in adult rat kidney. Like Nephrin and Podocin, Neph1 was enriched in Triton X-100 detergent-resistant membrane fractions. Consistent with this observation, immunogold electron microscopy demonstrated that Neph1 localized exclusively to lateral margins of podocyte foot processes at the insertion of the slit diaphragm. Neph1 and Nephrin participate in a direct cis-interaction involving their cytoplasmic domains. In addition, interactions between the extracellular domain of Nephrin and itself and between the extracellular domain of Nephrin and that of Neph1 were detected. Neph1 did not interact via a homophilic interaction. These observations suggest that Nephrin and Neph1 form a hetero-oligomeric receptor complex in the plane of the membrane that might interact across the foot process intercellular junction through interactions between Nephrin with itself and Neph1.

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“…The GBM has been thought to be the most important component in this size and charge selective sieving, and defects in the GBM have been regarded responsible for proteinuria in many glomerular diseases (2). Recent findings, however, have challenged the central role of the GBM in nephrotic diseases (3,4).Proteinuria is constantly associated with an effacement of podocyte foot processes, which has generally been regarded as a secondary phenomenon (5). Recent discoveries in the genetic diseases, however, suggest that podocytes may play a primary role in the development of proteinuria (6, 7).…”

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The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

Patrakka

2002

Pediatric Research

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The pathophysiology of proteinuria in acquired kidney diseases is mostly unknown. Recent findings in genetic renal diseases suggest that glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play an important role in the development of proteinuria. In this work we systematically evaluated the podocyte slit pores by transmission electron microscopy in two important nephrotic diseases, minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN). As controls, we used kidneys with tubulointerstitial nephritis (TIN). Effacement of podocyte foot processes was evident in proteinuric kidneys. However, quite normal looking foot processes and slit pores with varying width were also observed. Careful analysis of slit pores revealed, that the proportion of the pores spanned by the linear image of slit diaphragm, was reduced by 39% in kidneys from MCNS patients (1265 pores analyzed) compared with TIN samples (902 pores analyzed, p ϭ 0.0003). To enhance the detection rate of the slit diaphragms, the "empty" podocyte pores were further analyzed with tilting series from Ϫ45 to ϩ45. This revealed the linear diaphragm image in 71% and 26% of the slits in TIN and MCNS kidneys, respectively (p ϭ 0.0003). In contrast to findings in MCNS, no significant reduction of the slit diaphragms were seen in MN kidneys compared with the controls. The results suggest that MCNS is associated with disruption of glomerular slit diaphragms. The primary urine in the kidney forms by ultrafiltration of plasma components through the glomerular capillary wall into the urinary space (1). This glomerular filtration barrier is composed of a fenestrated endothelium, glomerular basement membrane (GBM) and epithelial cell (podocyte) layer. The podocyte layer consist intercalated foot processes, which are connected by 35-45 nm wide extracellular structure, termed the slit diaphragm. Normally, water and small plasma solutes filtrate easily through this sieve but the passage of proteins with the size of albumin and larger is almost completely restricted. The GBM has been thought to be the most important component in this size and charge selective sieving, and defects in the GBM have been regarded responsible for proteinuria in many glomerular diseases (2). Recent findings, however, have challenged the central role of the GBM in nephrotic diseases (3,4).Proteinuria is constantly associated with an effacement of podocyte foot processes, which has generally been regarded as a secondary phenomenon (5). Recent discoveries in the genetic diseases, however, suggest that podocytes may play a primary role in the development of proteinuria (6, 7). Mutations in NPHS1 gene coding for a podocyte specific protein, nephrin, are responsible for the congenital nephrotic syndrome of the Finnish type (NPHS1) (8, 9). Similarly, mutations in NPHS2 gene coding for another podocyte protein, podocin, are associated with a hereditary form of focal segmental glomerulosclerosis (FSGS) (10). Nephrin and podocin both localize at t...

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Genetic kidney diseases disclose the pathogenesis of proteinuria

Cited by 32 publications

References 62 publications

Tissue Expression of Nephrin in Human and Pig

Tissue Expression of Nephrin in Human and Pig

Nephrin and Neph1 Co-localize at the Podocyte Foot Process Intercellular Junction and Form cis Hetero-oligomers

The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

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