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Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–β–Dependent and –Independent Smad Pathways: The Role of Smad3
Abstract
Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)–mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II–induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-β1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II–induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II–induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-β–dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-β gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal–regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-β–independent, Ang II type 1 receptor–mediated extracellular signal–regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II–mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II–induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II–mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-β–dependent and –independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.
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Cited by
Cardiac Fibrosis: The Fibroblast Awakens
Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E., & Blaxall, B. C. (2016) · Circulation Research · doi:10.1161/circresaha.115.306565 · Cited by 1,596
Cellular and molecular mechanisms of renal fibrosis
Liu, Y. (2011) · Nature Reviews Nephrology · doi:10.1038/nrneph.2011.149 · Cited by 1,446
Chauhan, V. P., Martin, J. D., Liu, H., Lacorre, D. A., Jain, S. R., Kozin, S. V., Stylianopoulos, T., Mousa, A. S., Han, X., Adstamongkonkul, P., et al. (2013) · Nature Communications · doi:10.1038/ncomms3516 · Cited by 1,031
Renal tubule injury: a driving force toward chronic kidney disease
Liu, B.-C., Tang, T.-T., Lv, L.-L., & Lan, H.-Y. (2018) · Kidney International · doi:10.1016/j.kint.2017.09.033 · Cited by 913
Self-citationDiop-Frimpong, B., Chauhan, V. P., Krane, S., Boucher, Y., & Jain, R. K. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018892108 · Cited by 733
Metadata
- Authors
- Yang, F., Chung, A. C. K., Huang, X. R., & Lan, H. Y.
- Venue
- Hypertension
- Published
- 2009-10
- Volume
- 54
- Issue
- 4
- Pages
- 877-884
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2108806591
- Cited by
- 258
- References
- 0
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- closed
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- Yang, F., Chung, A. C. K., Huang, X. R., & Lan, H. Y. (2009). Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–β–Dependent and –Independent Smad Pathways: The Role of Smad3. Hypertension. https://doi.org/10.1161/hypertensionaha.109.136531
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