The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective

Abstract

Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators.

Keywords: cGMP; chronic kidney disease; nitric oxide; sGC; sGC activator; sGC stimulator; soluble guanylyl cyclase.

Figure 1

The NO/sGC and NP/pGC signaling cascade with major pharmacological intervention sites. NO/sGC- and NP/pGC-derived cGMP predominantly targets cGMP-dependent protein kinases (PKG/cGK), but also has mediates its actions though cyclic nucleotide-gated (CNG) ion channels and the activation or inhibition of phosphodiesterases (PDEs). The differential expression of enzyme isoforms in various cells and tissues, which mediate cellular effects, also have a direct impact on kidney function. The signaling cascade is currently targeted on the level of cGMP production (nitrates, sGC stimulators, and sGC activators) and cGMP degradation (PDE5 and PDE9 inhibitors). Abbreviations: ANP: Atrial natriuretic peptide; BNP: Brain natriuretic peptide; cGK: cGMP-dependent protein kinases; cGMP: cyclic guanosine monophosphate; CNG: Cyclic nucleotide-gated ion channels; CNP: C-type natriuretic peptide; GTP: cyclic guanosine triphosphate; GMP: guanosine monophosphate; NO: Nitric oxide; NOS: Nitric oxide synthase; NP: Natriuretic peptide; PDE: Phosphodiesterase; pGC: particulate guanylyl cyclase; PKG: Protein kinase G; sGC: Soluble guanylyl cyclase.

Figure 2

The cofactor heme is bound to sGC by various amino acids, but the central iron of heme builds a coordinative bound with the proximal histidine-105 (H105) of the sGC. Under oxidative conditions the heme iron changes to its Fe³⁺ state, resulting in a weakened sGC/heme bound and subsequently leading to the Apo form of sGC, which cannot be regulated by NO. Recent literature [1] indicates that oxidative stress can also lead to the formation of disulfide bridges normally absent in sGC and thereby affecting the function of the enzyme.

Figure 3

Schematic representation of a nephron and its functional units (glomerulus proximal tubulus, loop of Henle, distal tubulus and collecting duct and effects of NO/cGMP (increase/decrease: ↑/↓). (Nephron structure based on Servier Medical Art)