tracer experiments of the 1960s by Farquhar and Palade (8) using

tracer experiments of the 1960s by Farquhar and Palade (8) using ferritin a prototype of globular protein-like albumin established that glomerular capillaries in mammals serve while a barrier to the transglomerular passage of circulating large-molecular-weight plasma proteins since this tracer was mainly seen in proximity to glomerular endothelial fenestrae with no permeation into the glomerular basement membrane (GBM). lumina and did not enter the FAZF GBM; this suggested the GBM may K-Ras(G12C) inhibitor 6 serve as the main filtration barrier K-Ras(G12C) inhibitor 6 that discriminates their passage depending on their molecular excess weight or hydrodynamic radii. Simultaneous studies in the 1960s by Venkatachalam et al. (29 30 using peroxidatic tracers suggested the slit diaphragm rather than the GBM is the major barrier that restricts the passage of macromolecules across the GUU since some of them accumulated underneath the diaphragm. Therefore the controversy arose as to which component of the GUU the GBM versus slit diaphragm serves as the main filtration barrier. Amidst this contentious issue in the mid to late 1970s Brenner and colleagues (2) performed numerous fractional clearance experiments using varying sizes of neutral anionic and cationic dextrans and their results indicated the glomerular capillary wall behaves like a size- as well as charge-selective barrier. K-Ras(G12C) inhibitor 6 At the same time Venkatachalam and Farquhar and their colleagues (14 25 performed studies using cationic ferritin(s) and observed that this revised tracer could permeate deeper into the GBM and localize within its lamina rarae suggesting the GBM besides a size-selective barrier offers charge-selective properties. With respect to charge Venkatachalam et al. (27) also shown that intrarenal perfusion of solutions comprising basic compounds such as protamine sulfate (PS) led to a reversible fusion of the podocyte foot processes suggesting the podocyte surface also bears an electronegative charge and that its neutralization with PS led to their effacement. Therefore another controversy arose K-Ras(G12C) inhibitor 6 as to which component of the GUU the GBM versus podocytes foot processes is responsible for the charge-selective properties of the glomerular capillary and this observation was later on further compounded by the fact the endothelial cell surface also has a glycocalyx which in this equation might also impart to a certain extent the electronegative charge (6). An article by Sverrisson et al. (28) explored to what degree the GUU exerts size versus charge selectivity inside a PS perfusion model and if such properties are applicable to molecules with a wide range of hydrodynamic radii. In this regard a brief description of the structural and biochemical composition of the GUU may be obligatory to comprehend these controversies. The GUU of glomerular capillaries fractionates the blood into an ultrafiltrate that essentially includes small-molecular-weight proteins amino acids electrolytes and plasma water. Large-molecular proteins and cells are retained within the capillary lumina. The GUU is K-Ras(G12C) inhibitor 6 a stratified structure that is made up of an attenuated fenestrated endothelium facing the capillary lumina GBM and interdigitating foot processes of podocytes attached to the GBM and suspended in the urinary space (Fig. 1A) (16). The endothelial fenestrae are large circular openings of ≈100-nm diameter and allows a bulk circulation of intraluminal plasma solute to traverse without any impedance toward the GBM. The spaces between the interdigitating foot processes with an interdistance of ≈39 nm are spanned by thin membranes known as slit diaphragms that apparently restrict the transcapillary passage of macromolecules. They have a well-defined zipper-like substructure with 4 × 14-nm rectangular pores having effective restriction toward albumin which has a hydrodynamic diameter of ≈7.2 nm (26). On the other hand given the substructure sizes of the zipper its features is difficult to explain in terms of permeability of myoglobin which has an effective diameter of ≈4 nm but a sieving coefficient close to unity. This may be related to its additional biophysical characteristics i.e. an isoelectric point (pI) of ≈7.2 versus ≈4.9 for albumin. Intriguingly more recently slit diaphragms have been shown to include central ellipsoidal and circular pores with an average radius of ≈12 nm (9). These pores however seem to be quite large to impart any major restriction to albumin. The GBM that occupies the space between the cellular elements is an amorphous extracellular matrix (ECM) scaffold of ≈300 nm width and it is further stratified into a central dense layer known as the lamina densa that is flanked on either part by relatively loose electron lucent layers described as the lamina rara interna and externa. Fig. 1. A: electron micrograph of the ultrafiltration unit. It is made.