NO Signaling Through cGMP in Renal Tissue Fibrosis and Beyond: Key Pathway and Novel Therapeutic Target

Abstract

Nitric oxide (NO) produced by endothelial NO synthase (NOS) in low concentrations is a unique messenger molecule with key homeostatic functions concerning the prevention of pathological vascular and tissue changes such as increases in blood pressure, platelet degranulation, mononuclear cell infiltration, cell proliferation and extracellular matrix protein accumulation. This is in contrast to high levels of NO derived from inducible NOS which act as detrimental effector molecules and free radicals in immune response. Deficiency in NO's protective signaling actions is a major characteristic in numerous experimental and human disease situations. The main function of the NO signaling pathway is activation of the soluble guanylate cyclase (sGC) enzyme with subsequent generation of cyclic guanosine monophosphate (cGMP) as a second messenger and downstream mediator. In the past, attempts to overcome deficiency in endothelial NO effects were focused primarily on increasing the supply with the NO precursor L-arginine or on the use of directly NO-releasing compounds. The clinical impact of these strategies, however, was rather limited. Recent state-of-the-art studies have revealed that NO signaling is highly regulated at the transcriptional level and that deficiency in NO signaling correlates closely with pathological changes. In parallel efforts, novel pharmacological compounds which specifically enhance NO/cGMP signaling have been developed and have demonstrated remarkable efficacy in experimental disease settings. In this review, we summarize the current state of knowledge on the impairment of NO/cGMP signaling and about its pharmacological stimulation. In the first part, experimental renal fibrosis, i.e. the tandem rat model of acute anti-thy1 glomerulonephritis and progressive anti-thy1 renal fibrosis will serve as a paradigm for introducing this new and exciting field. In the second part, we will address the most recent findings on NO signaling in non-renal diseases. Together, these results point out that deficiency in NO/cGMP is a common key pathway as well as a novel therapeutic target in a number of diseases.

Nicorandil Improves Glomerular Injury in Rats With Mesangioproliferative Glomerulonephritis via Inhibition of Proproliferative and Profibrotic Growth Factors

“…L-Arginine, which activates the NO /cGMP signaling pathway, limits TGF-β overproduction and extracellular matrix accumulation in anti-Thy1 nephritis rats (16). In addition, it was reported that soluble guanylate cyclase (sGC) stimulators ameliorated renal function by inhibiting overexpression of TGF-β, collagen, and fibronectin via cGMP elevation in the acute and chronic anti-Thy1 nephritis rats (17,18). Nicorandil can also stimulate sGC and increase cGMP levels (19,20).…”

Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence

“…Three key pathways have been identified in promoting tissue matrix expansion: firstly, elevated synthesis of extracellular matrix components; secondly, increased inhibition of matrix degradation; and finally, upregulated local expression of integrins [11]. This pathogenic process is progressive and ultimately leads to ESRD [5].…”

Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat

“…Inasmuch as impaired autoregulation provides a risk factor for chronic renal failure, particularly in combination with hypertension (5), the findings also suggest safety with regard to chronic renal failure. In addition, cinaciguat and the structurally unrelated sGC activator ataciguat (HMR1766) have been shown to play a beneficial role in chronic kidney disease (4,35), presumably due to nonvascular effects ascribed to NO and cGMP on renal inflammation, fibrosis, and glomerulosclerosis (10,36,63).…”