Podocytes Are Firmly Attached to Glomerular Basement Membrane in Kidneys with Heavy Proteinuria

Abstract

Abstract. Glomerular epithelial cells (podocytes) play an important role in the pathogenesis of proteinuria. Podocyte foot process effacement is characteristic for proteinuric kidneys, and genetic defects in podocyte slit diaphragm proteins may cause nephrotic syndrome. In this work, a systematic electron microscopic analysis was performed of the structural changes of podocytes in two important nephrotic kidney diseases, congenital nephrotic syndrome of the Finnish type and minimalchange nephrotic syndrome (MCNS). The results showed that (1) podocyte foot process effacement was present not only in proteinuric glomeruli but also in nonproteinuric MCNS kidneys; (2) podocytes in proteinuric glomeruli did not show detachment from the basement membrane or cell membrane ruptures; (3) the number of pinocytic membrane invaginations in the basal and apical parts of the podocytes was comparable in proteinuric and control kidneys; (4) in proteinuric kidneys, the podocyte slit pore density was decreased by 69 to 80% and up to half of the slits were so "tight" that no visible space between foot processes was seen; thus, the filtration surface area between podocytes was dramatically reduced; and (5) in the narrow MCNS slit pores, nephrin was located in the apical part of the podocyte foot process, indicating vertical transfer of the slit diaphragm complex in proteinuria. In conclusion, these results suggest that protein leakage in the two nephrotic syndromes studied occurs through defective podocyte slits, and the other structural alterations commonly seen in electron microscopy are secondary to, not a prerequisite for, the development of proteinuria.The striking morphologic change in proteinuric kidneys is the replacement of discrete glomerular podocytic foot processes by large expanses of flattened epithelial cytoplasm. This abnormality was recognized in the earliest electron microscopic studies in the 1950s (1-3) and has constantly been described in human glomerular diseases as well as in animal models of proteinuria. The effacement of the foot processes has been regarded as an abnormal response of the epithelium either to direct injury or to alterations elsewhere in the glomerulus. The process is probably associated with changes in the actin cytoskeleton of the podocyte foot processes, but its molecular basis is still not known (4,5).The loss of the complex interdigitation of podocytes does not explain protein leakage in nephrotic kidneys. On the contrary, the wide expanses of epithelial cytoplasm often cover the glomerular basement membrane (GBM) of the capillary wall so that only occasional interruptions are present. These residual sites of previous slit pores may also show close apposition of adjacent podocyte cell membranes, forming "tight" or "close" junctions (6 -8). Thus, the total area available for the passage of the urinary ultrafiltrate in nephrotic kidney is probably much less than normal, and it is difficult to see how massive proteinuria occurs in such a situation.Two explanations have been offered to connec...

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