Podocyte

The inner wall of Bowman s capsule consists of specialized epithelial cells referred to as podocytes. This layer of epithelial cells is not continuous instead, the podocytes have foot-like processes that project outward. The processes of one podocyte interdigitate with the processes of an adjacent podocyte, forming narrow filtration slits. These slits provide an ample route for the filtration of fluid. 

In summary, the filtrate moves through the pores of the capillary endothelium, the basement membrane, and, finally, the filtration slits between the podocytes. This route of filtration is completely acellular. 

WT1 is present in the metanephric mesenchyme before induction and is upregulated during induction. Blocking induction stops the production of WT1. WT1 is expressed at high levels during the condensation of the mesenchyme and its transition to epithelium. Its expression diminishes thereafter, except in the podocyte layer of Bowman s capsule. WT1 knockout mice do not develop kidneys. The metanephric mesenchyme from these mice cannot be induced by wild-type inducers. 

After epithelialization and the formation of the S-shaped tubule, there is still much that needs to occur in order for the nephron to function. Cells destined to form the podocyte layer of the glomerulus flatten out and lose some of the markers that characterized their earlier transition to epithelium, including c-MYC, HOX-c9, LFB-1 and LFB-3, while keeping a high level of WT1. Expression of more classical mesenchymal markers such as vimentin takes place, but the cells also keep a number of epithelial proteins such as desmosomal components. The result is a tissue that is more organized than most connective tissue but leakier than most epithelium, the optimum design for urine filtration. 

Fetal urine is rich in serum proteins, as glomerular filtration begins before the podocyte layer of the glomerulus is mature. Although the proximal tubules have tight junctions and are capable of some endocytosis, there is insufficient capacity to resorb all of the filtered protein. The glomerular filtration barrier and proximal tubule resorption mature about 7 days after birth in the rat. 

Michaud, J. L., Lemieux, L. I., Dube, M., Vanderhyden, B. C., Robertson, S. J., and Kennedy, C. R. (2003). Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha aclinin-1. J. Am. Soc. Nephrol. 14, 1200-1211. 

Shirato, I., Hosser, H., Kimura, K., Sakai, T., Tomino, Y., and Kriz, W. (1996). The development of focal segmental glomerulosclerosis in masugi nephritis is based on progressive podocyte damage. Virchows Arch. 429, 255—273. 

Smoyer, W. E., Mundel, P., Gupta, A., and Welsh, M. J. (1997). Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am.J. Physiol. 273, F150-157. 

Harvey, S. J., Jarad, G., Cunningham, J., Rops, A. L., van der Vlag, J., Berden, J. H., et al. (2007) Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am J Pathol 171, 139-152. 

The glomerular capillary network lined with fenestrated endothelia is surrounded by the glomerular basement membrane and visceral epithelial cells (podocytes). Podocytes cover the outer aspect of the glomerular basement membrane with their... 

Plasma is filtered through a sieve consisting of three main layers (1) large endothelial fenestrations, (2) the dense network of the glomerular basement membrane, and (3) the slit diaphragm between podocyte processes. 

The glomerular basement membrane (GBM) forms the backbone of the glomerular tuft. It is composed of three layers lamina rara interna, lamina densa, and lamina rara externa. The glomerular basement membrane is composed of a network of collagen type IV molecules (H5) intertwined with nidogen to another network composed of molecules of laminin. Type IV collagen and laminin are responsible for the firmness of the glomerular basement membrane and enable adhesion of endothelial cells and podocytes as well. 

Podocytes are polarized cells, so one can differentiate between luminal and abluminal (basal) membrane domains (the basal domain corresponds to the sole plates of the foot processes, which are embedded in the basement membrane). The slit diaphragm forms the border between the luminal and the abluminal membranes. 

Fig. 1. Putative location of podocyte proteins mutated in different types of familial nephrotic syndrome.

Contractile elements of the podocyte foot processes, which may influence the hydraulic permeability of the glomerular capillary wall, may be regulated via vasoactive hormones. Receptors for some vasoactive hormones, for example, en-dothelin (R4), atrial natriuretic peptide (S9), nitric oxide (K22), and angiotensin n (Yl), have been described on the podocyte surface. 

Podocalyxin is the main sialoprotein on the surface of the podocyte body and the apex of podocytes above the level of the slit diaphragms (K16). Podocalyxin activation can be demonstrated in the later phase of glomerular development and immediately precedes the formation of urinary spaces. Podocalyxin is a type I membrane protein with four potential N-glycosylated sites and many potential sites for... 

Recently, several new podocyte-specific proteins have been identified nephrin, megalin, podoplanin, GLEPP-1, and synaptopodin. 

Further information about the function of these podocyte proteins and identification of further podocyte proteins and their interactions will clearly contribute to the better understanding of the mechanisms of proteinuria. 

Vasoactive hormones can influence the contractility and the structure of podocyte foot processes. An increase of intracellular calcium and cAMP in podocytes leads to contraction of foot processes and a decrease of Kf, whereas an increase of cGMP can act in the opposite direction (S9). Vasoactive hormones can also change the charge on the podocyte surface and so facilitate proteinuria (P2). 

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