Glomerular endothelium in kidneys with congenital nephrotic syndrome of the Finnish type (NPHS1)

Abstract

Background. The role of glomerular capillary endothelium in the pathophysiology of nephrotic kidney diseases is poorly known. We analysed the glomerular endothelial lesions in kidneys from patients with congenital nephrotic syndrome of the Finnish type (NPHS1). The disorder is caused by a genetic defect in a major podocyte slit diaphragm protein, nephrin. It manifests as nephrotic syndrome soon after birth and leads to glomerular sclerosis in early childhood. Methods. The glomerular capillary and endothelial cell lesions in NPHS1 kidneys nephrectomized at infancy were studied by electron and light microscopy, immunohistochemistry and cytokine antibody array. Results. Mesangial expansion and capillary obliteration were evident in practically all NPHS1 glomeruli. No thrombus formation was detected by fibrin staining. Electron microscopy revealed endothelial blebs (endotheliosis). The endothelial fenestration and the attachment of endothelial cells to the basement membrane were, however, quite normal. This fits to the abundant expression of a vascular endothelial growth factor (VEGF) and its transcription factor, hypoxia-inducible factor-1α (HIF-1α), in NPHS1 glomeruli. The proliferative activity of the intracapillary cells was modest and no apoptosis was detected. The expression of an endothelial adhesion molecule, intercellular adhesion molecule 1 (ICAM-1) and several chemokines was upregulated in NPHS1 glomeruli as compared to adult control kidneys. The recruitment of leukocytes carrying ligands for the major endothelial adhesion molecules, however, was modest in the mesangial area of NPHS1 glomeruli. Conclusions. The findings indicate that the glomerular endothelium is quite resistant to the nephrotic state in NPHS1 kidneys and underscores the importance of mesangial cells in the progression of glomerular sclerosis.

Vascular Endothelial Growth Factor Receptor 2 Direct Interaction with Nephrin Links VEGF-A Signals to Actin in Kidney Podocytes

“…VEGF-A is increased in congenital nephrotic syndrome of the Finnish type and in acquired glomerular diseases associated with nephrin down-regulation, such as diabetic nephropathy (7,29,30). Our studies also showed that podocyte-specific VEGF 164 gain of function during development causes nephrotic syndrome in mice (31) and in adult mice, leads to proteinuria, podocyte effacement, and loss of slit diaphragms (25).…”

Induction of Podocyte VEGF164 Overexpression at Different Stages of Development Causes Congenital Nephrosis or Steroid-Resistant Nephrotic Syndrome

“…These abnormalities are very similar to those described in nephrin-or podocin-null mice 11,32 and to podocyte and endothelial cell abnormalities described in kidneys from infants with CNSF. 9,33,34 This finding suggests that moderate podocyte VEGF 164 overexpression during organogenesis is sufficient to disrupt the development of mature podocyte foot processes, cell-cell interactions, and glomerular capillaries. VEGF-A is critical for fenestrae development and maintenance in mature glomerular endothelial cells.…”

“…8 VEGF is increased in congenital nephrotic syndrome of the Finnish type (CNSF). 9 Nephrin mutations cause CNSF, characterized by massive albuminuria at birth due to severe glomerular filtration barrier abnormalities. 10 Kidneys in CNSF fail to develop slitdiaphragms and podocyte foot processes are flattened and fused, 10,11 whereas associated mesangial expansion, endothelial blebs, and proliferation lead to capillary obliteration.…”

“…10 Kidneys in CNSF fail to develop slitdiaphragms and podocyte foot processes are flattened and fused, 10,11 whereas associated mesangial expansion, endothelial blebs, and proliferation lead to capillary obliteration. 9 Mutations in podocin, neph1, FAT1, WT1, and Nck1-2 genes also cause congenital nephrotic syndrome in mice, [12][13][14][15][16] suggesting that some integral components of the slit-diaphragm and nephrin signaling partners are crucial for the development and function of the glomerular filtration barrier, whereas others become critical for its maintenance.…”

Genotype–Phenotype Correlations in Non-Finnish Congenital Nephrotic Syndrome

“…Ultrastructural analysis of the glomerular capillary loops shows complete foot process effacement and swelling of endothelial cells. 11 NPHS1, encoding nephrin, was identified by positional cloning more than a decade ago and is the major gene involved in CNF in Finnish populations (98% of cases). 12 The Fin major (c.121delCT; p.L41fs) and Fin minor (c.3325CϾT; p.R1109X) mutations account for 78 and 16% of the mutated alleles, respectively, in Finnish cases 12 ; however, these mutations are rarely found in other ethnic groups.…”