Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

Abstract

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.

Association between high-altitude polycythemia and hypertension: a cross-sectional study in adults at Tibetan ultrahigh altitudes

“…The concentration of hemoglobin plays a key role in vascular function. As we know, hemoglobin is highly affinitized to nitric oxide (NO) [26], a molecule crucial for regulating arterial tone. In the HAPC population, a notable release of free hemoglobin occurs, resulting in the increased scavenging of NO, which is a major cause of high blood pressure [27].…”

Platelets in Renal Disease

“…Dysfunction of the endothelial cells can reduce NO synthesis [52][53][54], which may influence platelet reactivity [55]. Importantly, NO is involved in various physiological and pathological processes in the kidney [56,57]; therefore, changes in NO levels may affect the state of platelets in kidney diseases.…”

Title The Role of the Oxidative State and Innate Immunity Mediated by TLR7 and TLR9 in Lupus Nephritis

“…Changes in the distribution of NO sources due to altered expression of NOS subunits or shifts in the activity of NADPH oxidases can link or promote the development of pathologies. However, the mechanisms describing NO's production and release in glomerular cells, the interaction of NO and other ROS in podocytes, and how crosstalk between NO and calcium regulates glomerular cell function are still not fully described [92]. iNOS is upregulated in mouse models of LN and is overexpressed in the glomerulus in proliferative human LN [93].…”