Development of the Kidney Glomerular Filtration Barrier
Authors: Abrahamson Dale R. 
Published: June 2021

The kidney glomerular capillary wall filters blood plasma, yielding a dilute filtrate that is subsequently modified and concentrated by the nephron tubular epithelium during the process of urine formation. The glomerular filtration barrier itself consists of: (a) an inner fenestrated vascular endothelium; (b) outer epithelial podocyte layer with regular, interdigitating cytoplasmic extensions (foot processes) and associated slit diaphragms; and (c) an intervening basement membrane between the endothelial and podocyte layers (glomerular basement membrane [GBM]). This unique three‐layered structure restricts passage of plasma albumin, which, along with larger serum proteins, are retained in the circulation, and only trace amounts are normally found in the proximal filtrate.

Exactly how the filtration barrier operates is debated, but damage to any one layer results in loss of albumin and larger proteins into the urine (proteinuria), and, ultimately, can cause renal failure. Our work has focused on examining morphogenesis of the glomerulus and assembly of the GBM. To address these questions, and among other approaches, we grafted embryonic‐day 12 transgenic mouse kidneys bearing transcriptional reporters into newborn wildtype or mutant kidneys (where nephrogenesis is still underway), and examined the resulting hybrid tissues for mutation correction.

We and others showed that glomerular endothelial cells derive from angioblasts within metanephroi, podocytes develop from metanephric mesenchyme, and the GBM originates from fusion of subendothelial and sub‐podocyte basement membranes during glomerulogenesis. Further, the GBM of immature glomeruli contains collagen α1α2α1(IV) and laminin α1β1γ1. During glomerular maturation, these GBM isoforms are replaced by collagen α3α4α5(IV) and laminin α5β2γ1. Differentiating endothelial cells and podocytes synthesize collagen α1α2α1(IV) and both laminin isoforms, but collagen α3α4α5(IV) derives solely from maturing podocytes. Although mechanisms for collagen and laminin isoform substitutions are unknown, laminin transitioning is abrupt and precedes that for collagen IV, which occurs slowly. These developmentally distinct timetables suggest that different molecular and/or cellular controls account collagen IV and laminin isoform replacement.

Why the GBM undergoes compositional changes during glomerular formation is also uncertain, but this may be important for acquisition of glomerular barrier properties. Patients with mutations to COL4A3, A4, and/or A5, which are genes that encode collagen α3α4α5 (IV), usually develop Alport syndrome, a condition presenting with proteinuria, abnormal GBM composition and GBM delamination, loss of podocyte foot processes, and progressive renal failure. Studies on the Col4a3 knockout mouse, an experimental model of Alport disease, are shedding light on how the GBM informs glomerular barrier development and maintenance.

Support or Funding Information

Funds came from NIH grants P01DK065123 and P30GM122731.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.