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Organogenesis of the Kidney Glomerulus: Focus on the Glomerular Basement Membrane Jeffrey H

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Organogenesis of the Kidney Glomerulus: Focus on the Glomerular Basement Membrane Jeffrey H Washington University School of Medicine Digital Commons@Becker Open Access Publications 2011 Organogenesis of the kidney glomerulus: Focus on the glomerular basement membrane Jeffrey H. Miner Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Miner, Jeffrey H., ,"Organogenesis of the kidney glomerulus: Focus on the glomerular basement membrane." Organogenesis.7,2. 75-82. (2011). https://digitalcommons.wustl.edu/open_access_pubs/2536 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. ORGANOGENESIS FORUM ORGANOGENESIS FORUM Organogenesis 7:2, 75-82; April/May/June 2011; © 2011 Landes Bioscience Organogenesis of the kidney glomerulus Focus on the glomerular basement membrane Jeffrey H. Miner Renal Division; Department of Internal Medicine; Washington University School of Medicine; St. Louis, MO USA he glomerular basement membrane the approximately 900 L of blood that T(GBM) is a crucial component of the pass through them on a daily basis. Due kidney’s filtration barrier that separates to resorption of water and solutes by the the vasculature from the urinary space. tubular epithelial cells of the kidney, this During glomerulogenesis, the GBM is primary filtrate is concentrated to a uri- formed from fusion of two distinct base- nary output of only 1–2 L. The glomeru- ment membranes, one synthesized by lar filtration barrier, which lies between the glomerular epithelial cell (podocyte) the vasculature and the urinary space, and the other by the glomerular endo- retards the passage of plasma proteins, thelial cell. The main components of the primarily of albumin and immunoglob- GBM are laminin-521 (α5β2γ1), collagen ulins, while ensuring the efficient flow © 2011 Landes Bioscience. Landes ©2011 α3α4α5(IV), nidogen and the heparan of water and small solutes that comprise sulfate proteoglycan, agrin. By studying the primary filtrate. Since the realization Do not distribute. not Do mice lacking specific GBM components, that the glomerular capillary wall consists we have shown that during glomerulo- of two cells, podocyte and endothelium, genesis, laminin is the only one that is separated by an extracellular matrix called required for GBM integrity and in turn, the glomerular basement membrane the GBM is required for completion of (GBM), there have been vigorous debates glomerulogenesis and glomerular vascu- about which of these three layers serves as larization. In addition, our results from the major barrier to plasma proteins.1 In laminin β2-null mice suggest that lam- this review, I will summarize our current inin-521, and thus the GBM, contribute understanding of the cellular and extracel- to the establishment and maintenance of lular components of the glomerular capil- the glomerular filtration barrier to plasma lary wall and focus on the composition of albumin. In contrast, mutations that affect the GBM as it relates to glomerulogenesis, GBM collagen IV or agrin do not impair permselectivity and kidney disease. glomerular development or cause immedi- ate leakage of plasma proteins. However, Key words: laminin, collagen IV, The Glomerular collagen IV mutation, which causes nephrotic syndrome, alport syndrome, Filtration Barrier Alport syndrome and ESRD in humans, podocyte, mesangial cell, leads to gradual damage to the GBM The glomerular filtration barrier (Fig. 1) is glomerulogenesis that eventually leads to albuminuria and a three-layered structure that lies between Abbreviations: GBM, glomerular renal failure. These results highlight the the vasculature and Bowman’s space. basement membrane; LM, laminin; importance of the GBM for establishing Within the glomerulus, it is the only sepa- HSPG, heparan sulfate proteoglycan and maintaining a perfectly functioning, ration between the bloodstream and the Submitted: 02/24/11 highly selective glomerular filter. urine. The GBM is a specialized extracel- lular matrix situated between the podo- Accepted: 02/24/11 Introduction cytes and endothelial cells, which, during DOI: 10.4161/org.7.2.15275 glomerulogenesis, synthesize and secrete Correspondence to: Jeffrey H. Miner; Human kidneys generate an enormous components of the GBM. Furthermore, Email: [email protected] primary filtrate of about 180 liters from both cell types are important for www.landesbioscience.com Organogenesis 75 of filamentous plugs in the fenestrations. These plugs are thought to be composed of a form of glycocalyx (a sugary coat) assembled by the glomerular endothelial cells at their cell surfaces. These fenestral plugs have been hypothesized to serve as an impedance to the passage of plasma proteins and therefore an important com- ponent of the glomerular filtration barrier to albumin.8-10 Glomerular Basement Membrane (GBM) Figure 1. The ultrastructure of the glomerular filtration barrier. The capillary lumen is lined by The GBM is, in some ways, a typical base- an endothelium with fenestrations (arrowheads). The endothelium is adjacent to the ribbon-like ment membrane: it has an electron-dense glomerular basement membrane (GBM). Podocyte foot processes, which are bridged by slit dia- lamina densa when viewed by transmis- phragms (arrows), abut the opposite aspect of the GBM and are surrounded by the primary filtrate present in the urinary space. sion electron microscopy, and it is formed by protein-protein interactions among the same classes of macromolecules found in maintaining the GBM’s structure and and undergo a dramatic mesenchyme- all other basement membranes. However, function after glomerular maturation.2-4 to-epithelium transition to form what is the GBM also has some atypical features. Although the focus of this review is the referred to as the renal vesicle. Activation First, it is unusually thick compared to GBM, podocytes and endothelial cells of numerous important signaling path- most other basement membranes; as will also be discussed, as all three layers ways results in morphological changes to mentioned above, the GBM forms dur- are necessary for establishing and main- the renal vesicle and segmentation of the ing glomerulogenesis by the fusion of taining an intact filtrationBioscience. Landes ©2011 barrier. resulting “S-shaped” figure into the podo- two distinct basement membranes, the cytes, the parietal epithelial cells that form endothelial and the visceral epithelial Podocytes distribute. not Do Bowman’s capsule,and the epithelial cells (or podocyte) basement membranes.3 that comprise the tubular segments of the Second, the GBM has an unusual com- Podocytes, also called glomerular visceral nephron.6 position compared to most other base- epithelial cells, are morphologically com- ment membranes, and this presumably plex, nascent nephron epithelium-derived Glomerular Endothelial Cells imparts its unique functional properties. cells that reside within the urinary space The GBM contains laminin, type IV col- (also called Bowman’s space) and are Glomerular capillaries are lined by endo- lagen, nidogen and heparan sulfate pro- therefore bathed in the primary urine. thelial cells that are different than most, teoglycan (HSPG), components found in Podocytes enwrap the outer aspect of the because they bear many fenestrations all basement membranes, but for some of glomerular capillaries by extending nar- (Fig. 1). Fenestrations are seemingly pat- these types of matrix proteins, the specific row foot processes that interdigitate with ent “holes” in the endothelial cells that isoforms present in the GBM are very dif- those of adjacent podocytes. Juxtaposed allow the passage of fluid across the cell ferent than those found elsewhere in base- foot processes are directly linked to one layer. Ultrastructural analyses have shown ment membranes. Even the contiguous another by the glomerular slit diaphragms that some of these fenestrations have Bowman’s capsule and tubular basement (Fig. 1); these derive from gradual modi- wagon wheel-like diaphragms similar to membranes, for example, possess differ- fication and apical-to-basal migration of those found in peritubular capillaries and ent complements of isoforms compared to the tight junctions that originally joined in islet endothelial cells in the pancreas, the GBM. the previously columnar, immature but many of the fenestrations in glomer- The GBM occupies a prime position podocytes.5 ular endothelial cells do not have dia- within the glomerular filtration barrier Like the tubular epithelial cells of the phragms.7 This lack of diaphragms likely (Fig. 1). In addition, it is very dense by nephron, podocytes are descendants of allows more efficient flow of plasma across electron microscopy. Together with struc- the metanephric mesenchyme, a popula- this proximal layer of the glomerular fil- tural and functional data regarding the tion of intermediate mesoderm-derived tration barrier. GBM and other basement membranes, cells that are determined to form neph- Despite the presence of what usu- published by many different labs over a rons. At the beginning of development ally appear by electron microscopy to be period of decades, we hypothesize that the of the definitive kidney, the ureteric bud unobstructed fenestrae in the glomerular GBM functions by (1) providing adhesive grows towards and into the metanephric endothelium, special
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