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

Abstract

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...

Re-characterization of the Glomerulopathy in CD2AP Deficient Mice by High-Resolution Helium Ion Scanning Microscopy

“…6B–D ), the number of SD pores was reduced, and foot processes were shorter (Table 1 ) in the Cd2ap -KO kidneys. Reductions in the number and size of slit pores were previously observed in proteinuric animals and in nephrosis patients 29 , 38 , 39 . It has been proposed that slit pore reduction and foot process effacement may lead to high resistance and increased perfusion pressure across the filtration barrier, eventually causing barrier failure 40 .…”

Podocyte Dedifferentiation: A Specialized Process for a Specialized Cell

“…The number of slit diaphragms is reduced and the neat morphology of the podocyte is lost in nephrotic syndrome. This is clearly demonstrated by Patrakka et al ( 68 ). (D) Epithelial and mesenchymal features of the podocyte are shown.…”

The Pathology Lesion Patterns of Podocytopathies: How and why?

“…Foot process effacement is also associated with microfilament aggregation at the base of epithelial cells and filtration slit distortion, resulting in a reduction in the number of slit diaphragms ( Patrakka et al, 2002 ). This, in turn, causes a displacement of the diaphragms in a ladder-like formation toward the pore apex ( Patrakka et al, 2002 ).…”