Glomerular proteinuria: a complex interplay between unique players

Abstract

Protein leak in the urine is a harbinger of disruption of the glomerular filtration barrier. It also correlates with disease progression and development of ESRD. At present, therapies are aimed at decreasing proteinuria to decrease further damage to the filter and as a marker of remission. Understanding the mechanism of molecular events that lead to protein leak is vital to developing new therapeutic interventions. There has been tremendous progress over the last decade in identifying gene defects which result in hereditary proteinuric defects. This has led to identifying pathways by which these genes regulate the structure and function of the components of the filtration barrier, namely the podocytes, mesangial cells, endothelial cells, and the basement membrane. Using gene knockout mouse models, a role of tubular cells in regulating proteinuria is also emerging. In this review, we have attempted to present some of the prevailing understanding of the underlying mechanisms and physiology of proteinuria.

Figure 1

The glycocalyx contains anchoring proteoglycans (e.g. syndecan 1 and CD44) and connecting glycosoaminoglycans (e.g. heparan sulfate, chondroitin sulfate and hyaluronic acid). The negative charge of the proteins constitutes an important charge barrier against filtration of albumin. During endothelial activation, the glycocalyx is modified to allow leukocytes and platelets to interact with the endothelial surface. Glycocalyx components are then modified and released into the circulation. With prolonged activation and early apoptotic events, adhesion molecules such as E-selectin may also be shed. (Reprinted by permission from Nature review Nephrology).

Figure 2. Glomerular filtration barrier and tubules

A. Nephrin/Neph1 tyrosine phosphorylation dependent recruitment of protein complexes involved in actin regulation. Fyn mediated tyrosine phosphorylation of Neph1 on Y637 and Y638 results in recruitment of adaptor protein Grb2. Similarly nephrin phosphorylation on its tyrosine residues Y1191, Y1208 and Y1232 recruits Nck, Crk (Y1198 and Y1225) and P85 subunit (Y1128, Y1153 and Y1154) of PI3 kinase. B. Schematic cross section of podocyte foot process, glomerular basement membrane and endothelial cells. Also illustrated are the important proteins (mutations or deletions) which have been identified to result in proteinuria in human diseases or mouse models. C. Schematic of the nephron with the proximal tubule illustrating tubular proteins cubulin and megalin. Abbreviations: TrpC6, transient receptor potential C6; nWasp: neural Wiskott Aldrich syndrome protein; Arp2/3: actin related protein 2 and 3; AT1 receptor: Angiotensin receptor 1; SSH1: slingshot 1; PPase: phosphatase.