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.

Keywords: glomerulus; hypertension; lupus nephritis; nitric oxide synthase.

Figure 1

Merged fluorescent and transmitted light images of freshly isolated decapsulated glomeruli loaded with DAF-FM dye (ex. 488, em. 510/20 nm). Microphotographs show the surface localization of podocytes in the glomerulus. Confocal imaging of glomerulus before (left panels) and after (right panels) application of Ang II (a) or H₂O₂ (b) provoke elevation of intracellular NO levels in podocytes. Arrows denote podocytes discernable by their morphology and location. The scale bar is 20 μm.

Figure 2

The proposed role of NOS2 in nitrosative stress and pathogenesis of podocyte and glomerular diseases. Under pathological conditions such as hyperglycemia, cellular production of NO and reactive oxygen species (ROS) are increased, promoting peroxynitrite (ONOO⁻) production [50]. Peroxynitrite and other reactive nitrogen species oxidatively inactivate different mitochondrial proteins, affecting the iron–sulfur centers and altering mitochondria function. Alternatively, nitrosative stress results in NOS uncoupling, further increasing O²⁻ production and oxidative stress [51]. Overall, the cascade of events may alter mitochondria activity and promote redox imbalance leading to irreversible damage and podocyte dysfunction.

Figure 3

Genotype-tissue expression data for NO synthases in the human kidney cortex of males and females. Data were obtained from the GTEX portal (dbGaP Accession phs000424.v8.p2, 12 May 2022). Sample size: female n = 19; male n = 66.

Figure 4

Proposed angiotensin II and H₂O₂-induced NO elevation in podocytes. Angiotensin-II metabolites may activate production of NO in cells through AT2R or Mas receptors [70,71]. Activation of this GPCR is followed by PI3-K/Akt-dependent NOS phosphorylation and subsequent NO production [71,72]. Angiotensin II binds to its receptors and activates NADPH oxidase, which in turn increases ROS generation. NADPH oxidases, such as NOX4, mediate H₂O₂ release, which may further promote PI3-K/Akt-dependent NOS phosphorylation and subsequent NO production [73].