Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular ultrafiltration, vasodilation, and inflammation. Changes in NO bioavailability in pathophysiological conditions such as hypertension or diabetes may lead to podocyte damage, proteinuria, and rapid development of chronic kidney disease (CKD). Despite the extensive data highlighting essential functions of NO in health and pathology, related signaling in glomerular cells, particularly podocytes, is understudied. Several reports indicate that NO bioavailability in glomerular cells is decreased during the development of renal pathology, while restoring NO level can be beneficial for glomerular function. At the same time, the compromised activity of nitric oxide synthase (NOS) may provoke the formation of peroxynitrite and has been linked to autoimmune diseases such as systemic lupus erythematosus. It is known that the changes in the distribution of NO sources due to shifts in NOS subunits expression or modifications of NADPH oxidases activity may be linked to or promote the development of pathology. However, there is a lack of information about the detailed mechanisms describing the production and release of NO in the glomerular cells. The interaction of NO and other reactive oxygen species in podocytes and how NO-calcium crosstalk regulates glomerular cells’ function is still largely unknown. Here, we discuss recent reports describing signaling, synthesis, and known pathophysiological mechanisms mediated by the changes in NO homeostasis in the podocyte. The understanding and further investigation of these essential mechanisms in glomerular cells will facilitate the design of novel strategies to prevent or manage health conditions that cause glomerular and kidney damage.

The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function.

Protease-activated receptors (PARs) are a subclass of G protein-coupled receptors activated by serine proteases via proteolytic cleavage, triggering intracellular signaling cascades that regulate various physiological processes. Recent research underscores the significance of serine proteases and PARs in renal physiology, particularly in glomerular cells, where they modulate podocyte function, mesangial matrix dynamics, and filtration barrier integrity. In this review, we discuss the current knowledge on the function of key serine proteases in the kidney and their interactions with specific PARs, with a focus on the glomerulus and pathological implications. Among PARs, PAR1 is the most abundantly expressed in the kidney and plays a pivotal role in renal pathology. Serine proteases such as thrombin, plasmin, and kallikrein interact with PARs to regulate renal function; however, dysregulation in this pathway may contribute to diabetic nephropathy, glomerulosclerosis, fibrosis, and chronic kidney disease. Overall, the role of PARs in glomerular pathophysiology represents a critical area of research with significant therapeutic implications. Continued investigation into the mechanisms of serine proteases and PARs is essential for advancing targeted therapies for glomerular disorders.

Endothelial cells contribute to the development of renal inflammation and have the unique ability to express antigen presentation proteins. Whether increased endothelial mechanical stretch regulates immunological synapse interface proteins remains unknown. We found that antigen presentation proteins and costimulatory proteins on renal endothelial cells are modulated by mechanical stretch in a sex-dependent manner. Our data provide novel insights into the sex-dependent ability of renal endothelial cells to present antigens in response to endothelial mechanical stimuli.

Our study demonstrated novel pathways affecting glomeruli under stress induced by dietary salt. Predictive gene correlation networks and bioinformatic semi-automatic analysis revealed changes in the pathways relevant to mitochondrial function, inflammatory, apoptotic/fibrotic processes, and cell calcium transport.