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Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways.
Am J Physiol Renal Physiol. 2010 Sep; 299(3):F585-93.AJ

Abstract

Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7.

Authors+Show Affiliations

Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20554647

Citation

Burns, W C., et al. "Angiotensin II Mediates Epithelial-to-mesenchymal Transformation in Tubular Cells By ANG 1-7/MAS-1-dependent Pathways." American Journal of Physiology. Renal Physiology, vol. 299, no. 3, 2010, pp. F585-93.
Burns WC, Velkoska E, Dean R, et al. Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways. Am J Physiol Renal Physiol. 2010;299(3):F585-93.
Burns, W. C., Velkoska, E., Dean, R., Burrell, L. M., & Thomas, M. C. (2010). Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways. American Journal of Physiology. Renal Physiology, 299(3), F585-93. https://doi.org/10.1152/ajprenal.00538.2009
Burns WC, et al. Angiotensin II Mediates Epithelial-to-mesenchymal Transformation in Tubular Cells By ANG 1-7/MAS-1-dependent Pathways. Am J Physiol Renal Physiol. 2010;299(3):F585-93. PubMed PMID: 20554647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways. AU - Burns,W C, AU - Velkoska,E, AU - Dean,R, AU - Burrell,L M, AU - Thomas,M C, Y1 - 2010/06/16/ PY - 2010/6/18/entrez PY - 2010/6/18/pubmed PY - 2010/9/25/medline SP - F585 EP - 93 JF - American journal of physiology. Renal physiology JO - Am J Physiol Renal Physiol VL - 299 IS - 3 N2 - Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7. SN - 1522-1466 UR - https://www.unboundmedicine.com/medline/citation/20554647/Angiotensin_II_mediates_epithelial_to_mesenchymal_transformation_in_tubular_cells_by_ANG_1_7/MAS_1_dependent_pathways_ L2 - https://journals.physiology.org/doi/10.1152/ajprenal.00538.2009?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -