NAD(P)H Oxidase Mediates TGF-β1–Induced Activation of Kidney Myofibroblasts
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TGF-beta1 expression closely associates with activation and conversion of fibroblasts to a myofibroblast phenotype and synthesis of an alternatively spliced cellular fibronectin variant, Fn-ED-A. Reactive oxygen species (ROS), such as superoxide, which is a product of NAD(P)H oxidase, also promote the transition of fibroblasts to myofibroblasts, but whether these two pathways are interrelated is unknown. Here, we examined a role for NAD(P)H oxidase-derived ROS in TGF-beta1-induced activation of rat kidney fibroblasts and expression of alpha-smooth muscle actin (alpha-SMA) and Fn-ED-A. In vitro, TGF-beta1 stimulated formation of abundant stress fibers and increased expression of both alpha-SMA and Fn-ED-A. In addition, TGF-beta1 increased both the activity of NADPH oxidase and expression of Nox2 and Nox4, homologs of the NAD(P)H oxidase family, indicating that this growth factor induces production of ROS. Small interfering RNA targeted against Nox4 markedly inhibited TGF-beta1-induced stimulation of NADPH oxidase activity and reduced alpha-SMA and Fn-ED-A expression. Inhibition of TGF-beta1 receptor 1 blocked Smad3 phosphorylation; reduced TGF-beta1-enhanced NADPH oxidase activity; and decreased expression of Nox4, alpha-SMA, and Fn-ED-A. Diphenyleneiodonium, an inhibitor of flavin-containing enzymes such as the Nox oxidases, had no effect on TGF-beta1-induced Smad3 but reduced both alpha-SMA and Fn-ED-A protein expression. The Smad3 inhibitor SIS3 reduced NADPH oxidase activity, Nox4 expression, and blocked alpha-SMA and Fn-ED-A, indicating that stimulation of myofibroblast activation by ROS is downstream of Smad3. In addition, TGF-beta1 stimulated phosphorylation of extracellular signal-regulated kinase (ERK1/2), and this was inhibited by blocking TGF-beta1 receptor 1, Smad3, or the Nox oxidases; ERK1/2 activation increased alpha-SMA and Fn-ED-A. Taken together, these results suggest that TGF-beta1-induced conversion of fibroblasts to a myofibroblast phenotype involves a signaling cascade through Smad3, NAD(P)H oxidase, and ERK1/2.
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Although NOX4 activity has been shown to reduce fibrosis in atherosclerosis, it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues.
“In a final note, it should be also considered that although NOX4 activity has been shown to reduce fibrosis in atherosclerosis (230), it can also promote fibrosis, particularly in the lung, but also in kidney and other tissues (110, 201, 416, 596, 820).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [110]
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- Authors
- Bondi, C. D., Manickam, N., Lee, D. Y., Block, K., Gorin, Y., Abboud, H. E., & Barnes, J. L.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- Journal of the American Society of Nephrology
- Published
- 2010-01
- Volume
- 21
- Issue
- 1
- Pages
- 93-102
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC2799274
- OpenAlex
- W2142742192
- Cited by
- 297
- References
- 68
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 14 · 2023: 17 · 2022: 15 · 2021: 11 · 2020: 15 · 2019: 16 · 2018: 17 · 2017: 21 · 2016: 28 · 2015: 17 · 2014: 26 · 2013: 30 · 2012: 32
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080106, R01DK078971, P50DK061597)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- NADPH oxidase, TGF-β1, myofibroblast activation, kidney fibroblasts, reactive oxygen species, NOX4, NOX2, Smad3, ERK1/2, alpha-smooth muscle actin, renal fibrosis, stress fibers, diphenyleneiodonium
- MeSH terms
- NADPH Oxidase 2, NADPH Oxidase 4, Actins, Animals, Cell Differentiation, Cell Line, Fibroblasts, Fibronectins, Membrane Glycoproteins, Signal Transduction, Reactive Oxygen Species, NADPH Oxidases, Mitogen-Activated Protein Kinase 1, Models, Animal, Mitogen-Activated Protein Kinase 3, Rats, Smad3 Protein, Transforming Growth Factor beta1
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