The Glomerular Endothelium Restricts Albumin Filtration

Abstract

Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.

New insights into proteinuria/albuminuria

“…The endothelial glycocalyx has also been targeted as a factor having significant influence in ultrafiltration ( Ballermann et al, 2021 ). This region is >95% water yet there are claims by various groups ( Ballermann et al, 2021 ; van den Berg et al, 2019 ; Butler et al, 2020 ) that the endothelial glycocalyx plays a critical role in albumin filtration across the GFB.…”

Commentary: The Glomerular Endothelium Restricts Albumin Filtration

“…Contrary to the claims of Ballermann et al (1) that "the glomerular endothelium bars the bulk of albumin from passing to the ultrafiltrate, " the results from the famous physiologist/thermodynamicist AG Ogston and his colleagues at Oxford would make you argue the opposite. Ogston and Preston measured the two types of albumin interaction with glycosaminoglycan chains (the major constituent of the endothelium) including equilibrium interactions reflecting excluded volume (2,3) and transport interactions representing dynamic interactions (4) under physiological conditions.…”

“…Ballermann et al ( 1 ) also surprisingly continue to cite work from Haraldsson's group ( 6 – 9 ) on the cold isolated kidney perfusion (cIPK) technique. The technique has been discredited for some time ( 10 ) particularly in relation to apparent “charge selectivity” without the criticism being addressed.…”

Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage

“…Since albuminuria develops as a consequence of impaired glomerular filtration barrier permselective function, we explored whether the worsening effect of Sirt3 deficiency on urinary albumin excretion in response to HFD could be related to functional and/or structural changes in podocytes and glomerular endothelial cells, which are the main determinants of the glomerular filtration barrier [ 22 , 23 ]. Our analysis of nestin, a protein found in the podocyte cytoskeleton, which plays an important role in maintaining podocyte function [ 24 ], revealed reduced staining in the glomeruli of WT mice fed with HFD instead of a standard diet.…”