NMDA Receptor Hypofunction in the Aging-Associated Malfunction of Peripheral Tissue

Glutamatergic transmission through NMDA receptors (NMDARs) is important for the function of peripheral tissues. In the bone, NMDARs and its co-agonist, D-serine participate in all the phases of the remodeling. In the vasculature, NMDARs exerts a tonic vasodilation decreasing blood perfusion in the corpus cavernosum and the filtration rate in the renal glomerulus. NMDARs are relevant for the skin turnover regulating the proliferation and differentiation of keratinocytes and the formation of the cornified envelope (CE). The interference with NMDAR function in the skin leads to a slow turnover and repair. As occurs with the brain and cognitive functions, the manifestations of a hypofunction of NMDARs resembles those observed during aging. This raises the question if the deterioration of the glomerular vasculature, the bone remodeling and the skin turnover associated with age could be related with a hypofunction of NMDARs. Furthermore, the interference of D-serine and the effects of its supplementation on these tissues, suggest that a decrease of D-serine could account for this hypofunction pointing out D-serine as a potential therapeutic target to reduce or even prevent the detriment of the peripheral tissue associated with aging.

Pathomorphological picture of diabetic nephropathy in experimental diabetes mellitus

Aim. To conduct a morphological study of the renal glomerulus in experimental diabetes mellitus and to study the pathomorphological features of the development of diabetic nephropathy. Methods. The study was carried out on 25 male Wistar rats. Modeling of diabetes mellitus was carried out by intraperitoneal injection of streptozotocin at a dose of 65 mg/kg. For more selective modeling of type 2 diabetes, the rats of the control group were intraperitoneally administered a solution of cytoflavin, calculated by the dosage of nicotinamide 115 mg/kg. In the comparison group 1 ml of physiological solution was administered in a similar manner. On day 28 of the experiment, the animals were euthanized under ether anesthesia, the kidneys were extracted, purified and washed with physiological saline. The material was fixed in a 10% neutral formalin solution. Using the morphometric method, the area of the renal glomeruli and the area of the capillary lumens were measured, and after special computer processing of digital photographs, the total area of the vascular bed in the glomerulus and the area of mesangium in the renal glomerulus were estimated. Results. After four weeks of experiment on rats with diabetes mellitus, some characteristic changes in the morphofunctional state of renal tissues developed: an increase of the area of renal glomeruli, thickening of the basement membrane of glomerular capillaries, an increase in the size of podocytes with a decrease of their number, and foci of nephrosclerosis. Conclusion. Based on the results of the study, characteristic pathomorphological phenomena in the kidneys of rats with experimental diabetes mellitus were recorded, which indicate the development of diabetic nephropathy.

A Review of Podocyte Biology

Background: Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement. Summary: Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting.