The glomerular filtration barrier: components and crosstalk

Abstract

The glomerular filtration barrier is a highly specialized blood filtration interface that displays a high conductance to small and midsized solutes in plasma but retains relative impermeability to macromolecules. Its integrity is maintained by physicochemical and signalling interplay among its three core constituents-the glomerular endothelial cell, the basement membrane and visceral epithelial cell (podocyte). Understanding the pathomechanisms of inherited and acquired human diseases as well as experimental injury models of this barrier have helped to unravel this interdependence. Key among the consequences of interference with the integrity of the glomerular filtration barrier is the appearance of significant amounts of proteins in the urine. Proteinuria correlates with kidney disease progression and cardiovascular mortality. With specific reference to proteinuria in human and animal disease phenotypes, the following review explores the roles of the endothelial cell, glomerular basement membrane, and the podocyte and attempts to highlight examples of essential crosstalk within this barrier.

Figure 1

Components of the Glomerular filtration barrier with examples of crosstalk. This figure summarizes important signaling interactions between the 3 key components of the GFB and their putative involvement in human disease models (dotted arrows). Podocyte α3-β1 integrin interacts with GBM β-2 laminin; hyposialylated-podocyte-secreted Angp-4 may have an effect on the GBM and the endothelial cell in MCD models. sUPAR, a potential circulating “serum factor,” affects podocyte αV-β3 integrin in primary FSGS. Podocyte-endothelial cell interactions are affected by VEGF/VEGF-R blocking agents in preecclampsia while SDF-1-CXCR4 pathway is perturbed by Shiga toxins in HUS. Alternate pathway complement dysregulation and consequent endothelial components are central to MPGN and atypical HUS.