NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses

Abstract

Uncontrolled fibrosis in organs like heart, kidney, liver and lung is detrimental and may lead to end-stage organ failure. Currently there is no effective treatment for fibrotic disorders. Transforming growth factor (TGF)-β has a fundamental role in orchestrating the process of fibrogenesis; however, interventions directly targeting TGF-β would have undesired systemic side effects due to the multiple physiological functions of TGF-β. Further characterization of the downstream signaling pathway(s) involved in TGF-β-mediated fibrosis may lead to discovery of novel treatment strategies for fibrotic disorders. Accumulating evidence suggests that Nox4 NADPH oxidase may be an important downstream effector in mediating TGF-β-induced fibrosis, while NADPH oxidase-dependent redox signaling may in turn regulate TGF-β/Smad signaling in a feed-forward manner. It is proposed that pharmacological inhibition of the Nox4 function may represent a novel approach in treatment of fibrotic disorders.

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

“…In this respect, GKT137831 is a pyrazolopyridine dione derivative and first in‐class potent and orally bioavailable dual Nox1/Nox4 inhibitor that displays excellent pharmacological and safety profiles 30. Consistent with the many molecular and cellular parallels between the desmoplastic stromal response in solid tumors and perturbed wound healing process in fibrosis,46 a TGFβ1‐Nox4 signaling axis has emerged as a common denominator in the activation of mesenchymal cells from numerous tissues with elevated Nox4 expression implicated in the pathophysiology of various fibrotic conditions 47. Consequently, GKT137831 is currently undergoing clinical trials following antifibrogenic effects in in vitro and in vivo experimental models of idiopathic pulmonary fibrosis, diabetic nephropathy, hepatic fibrosis and retinal inflammation 30, 48, 49, 50.…”

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

“…TGF‐β1 stimulates the production of ROS by promoting expression of NADPH oxidase‐4 (NOX‐4) in a SMAD3‐dependent manner (Hecker et al, 2009; Jiang, Liu, Dusting, & Chan, 2014; Sampson et al, 2011). While TGF‐β1‐induced myofibroblast transdifferentiation involves the production of such ROS, the mechanisms how these reactive molecules facilitate transdifferentiation are still obscure.…”

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

“…A characteristic feature of Nox4-related signaling is the presence of positive feedback loops, wherein Nox4 is both a downstream target and an upstream activator of a particular pathway (71). Thus, whereas TGF␤ is a prime inducer of Nox4 expression, Nox4-derived ROS facilitated TGF␤ signaling both by promoting the liberation of active TGF␤ from the latent complex (72) and by enhancing TGF␤-induced Smad2/3 phosphorylation (19).…”