The Physiology of the Glomerular Tuft Structure • The glomerulus consists of a capillary tuft that is surrounded by Bowman's capsule, which passes the filtered primary urine to the tubular system. • It is a network held together by connective tissue and composed of three distinct cell types: endothelial cells, mesangial cells, and glomerular visceral epithelial cells (podocytes). • Glomerular filtration barrier is a trilaminar structure composed of a fenestrated endothelium, the hydrated meshwork of the glomerular basement membrane (GBM), and the filtration slit formed by pedicel interdigitation. Mesangial Cells • There are two distinct populations of mesangial cells. • The first population makes up about 85% to 95% of resident mesangial cells and has a network of contractile elements, such as actin, myosin, and tropomyosin. • The second population exhibit features of monocytes/macrophages and are derived from bone marrow. • The covering of the capillaries by the GBM is partial. • Mesangial cells account for the completion of the capillary covering by forming loops that completely encircle the capillaries. • Those contacts establish a biomechanical unit, with the basement membrane serving as the effector site and mesangial cells as the contractile motor. • These contacts permit the mesangial cells to support the mesangium and regulate the capillary surface area and glomerular volume, influencing glomerular hemodynamics. • Therefore, mesangial cells can modulate GFR by changing the capillary surface area and redistributing blood volume in glomerular capillaries through the actions of mesangial loops. • Contraction of a mesangial cell occurs in response to hormones, vasoactive compounds, and growth factors through G protein–associated receptors that activate phospholipase C. • Hormones using the cyclic AMP and cyclic GMP cascades relax mesangial cells through direct effects or through antagonism of contracting substances. Glomerular Filter • Endothelial Cell – The glomerular endothelial fenestrae may be covered by a diaphragm formed by a thick cell coat (glycocalyx). – This layer is a matrix-like gel composed of proteoglycans, with negatively charged as well as neutral glycosaminoglycans, glycoproteins, and plasma proteins carrying a negative charge. – Thus, the glycocalyx is an initial charge barrier in the glomerular filter and function as a size-selective barrier. • Glomerular Basement Membrane – The GBM is an especially thick membrane that lies between the endothelial cells and the visceral epithelium (podocytes). – The main components of the GBM are triplehelical type IV collagen, proteoglycans, laminin, and entactin. • Glomerular Visceral Epithelial Cells (Podocytes) – Podocytes can be divided into three distinct functional segments: cell body, primary processes, and secondary processes, also known as foot processes or pedicels. – These cells are located at the external surfaces of glomerular capillaries, which they cover with pedicels. – The covering of capillaries is achieved by interdigitation of pedicels derived from adjacent podocytes, forming between them filtration slits that are bridged by a specialized cell junction, called slit diaphragms, which represent the last filtration barrier to proteins. – The cell body and primary processes are mainly constituted by microtubules and intermediate filaments, whereas pedicels contain a dense network of actin microfilament bundles associated with myosin II, α-actin, talin, and vinculin, forming a complex contractile apparatus. – Podocytes have all the necessary elements to generate tensile strength and stabilize glomerular architecture by counteracting the hydrostatic forces causing distentions of glomerular capillaries. – Podocytes also have receptors for several contracting and relaxing factors. – The slit diaphragm not only provides a structural element, serving as a static molecular sieve, but also is a dynamic multifunctional protein complex that functions as a signalling platform for the podocyte. – Podocytes seem to play a crucial role in the development of the entire glomerular tuft, mainly through production of angiogenic factors. – During glomerular development, they express vascular endothelial growth factor-A (VEGF-A), whereas the endothelial and mesangial cells express the VEGF receptors.