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Published in: BMC Complementary Medicine and Therapies 1/2017

Open Access 01-12-2017 | Research article

The Hippo signaling pathway: a potential therapeutic target is reversed by a Chinese patent drug in rats with diabetic retinopathy

Authors: Gai-mei Hao, Tian-tian Lv, Yan Wu, Hong-liang Wang, Wei Xing, Yong Wang, Chun Li, Zi-jian Zhang, Zheng-lin Wang, Wei Wang, Jing Han

Published in: BMC Complementary Medicine and Therapies | Issue 1/2017

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Abstract

Background

The Hippo signaling pathway is reported to be involved in angiogenesis, but the roles of the Hippo pathway in diabetic retinopathy have not been addressed. Fufang Xueshuantong Capsule has been used to treat diabetic retinopathy in China; however, the effect of Fufang Xueshuantong Capsule on the Hippo pathway has not been investigated.

Methods

In this study, diabetes was induced in Sprague-Dawley rats with intraperitoneal injection of streptozotocin. Twenty weeks later, Fufang Xueshuantong Capsule was administered for 12 weeks. When the administration ended, the eyes were isolated for western blot and immunohistochemistry analyses. The levels of P- mammalian sterile 20-like (MST), large tumor suppressor homolog (Lats), P- yes-associated protein (YAP), transcriptional co-activator with PDZ binding motif (TAZ) and TEA domain family members (TEAD) were measured.

Results

Diabetic rats had a decreased P-MST level in the inner plexiform layer and reduced expression of P-YAP in the photoreceptor layers of their eyes. In addition, diabetic rats displayed remarkable increases in Lats, TAZ and TEAD in their retinas. Furthermore, Fufang Xueshuantong Capsule restored the changes in the Hippo pathway.

Conclusions

The Hippo signaling pathway is important for the progression of diabetic retinopathy and will hopefully be a targeted therapeutic approach for the prevention of diabetic retinopathy.
Appendix
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Literature
1.
go back to reference Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ. Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia. 2005;48(11):2422–7.CrossRefPubMed Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ. Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia. 2005;48(11):2422–7.CrossRefPubMed
2.
go back to reference Stitt AW, Lois N, Medina RJ, Adamson P, Curtis TM. Advances in our understanding of diabetic retinopathy. Clin Sci (Lond). 2013;125(1):1–17.CrossRef Stitt AW, Lois N, Medina RJ, Adamson P, Curtis TM. Advances in our understanding of diabetic retinopathy. Clin Sci (Lond). 2013;125(1):1–17.CrossRef
3.
go back to reference Titchenell PM, Antonetti DA. Using the past to inform the future: anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy. Diabetes. 2013;62(6):1808–15.CrossRefPubMedPubMedCentral Titchenell PM, Antonetti DA. Using the past to inform the future: anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy. Diabetes. 2013;62(6):1808–15.CrossRefPubMedPubMedCentral
4.
5.
go back to reference Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.CrossRefPubMed Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13(4):246–57.CrossRefPubMed
6.
go back to reference Mauviel A, Nallet-Staub F, Varelas X. Integrating developmental signals: a Hippo in the (path)way. Oncogene. 2012;31(14):1743–56.CrossRefPubMed Mauviel A, Nallet-Staub F, Varelas X. Integrating developmental signals: a Hippo in the (path)way. Oncogene. 2012;31(14):1743–56.CrossRefPubMed
7.
go back to reference Zhou X, Wang Z, Huang W, Lei QY. G protein-coupled receptors: bridging the gap from the extracellular signals to the Hippo pathway. Acta Biochim Biophys Sin Shanghai. 2015;47(1):10–5.CrossRefPubMed Zhou X, Wang Z, Huang W, Lei QY. G protein-coupled receptors: bridging the gap from the extracellular signals to the Hippo pathway. Acta Biochim Biophys Sin Shanghai. 2015;47(1):10–5.CrossRefPubMed
8.
go back to reference Dai X, She P, Chi F, Feng Y, Liu H, Jin D, Zhao Y, Guo X, Jiang D, Guan KL, et al. Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration, and angiogenesis. J Biol Chem. 2013;288(47):34041–51.CrossRefPubMedPubMedCentral Dai X, She P, Chi F, Feng Y, Liu H, Jin D, Zhao Y, Guo X, Jiang D, Guan KL, et al. Phosphorylation of angiomotin by Lats1/2 kinases inhibits F-actin binding, cell migration, and angiogenesis. J Biol Chem. 2013;288(47):34041–51.CrossRefPubMedPubMedCentral
9.
10.
go back to reference Xie C, Guo Y, Zhu T, Zhang J, Ma PX, Chen YE. Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin. J Biol Chem. 2012;287(18):14598–605.CrossRefPubMedPubMedCentral Xie C, Guo Y, Zhu T, Zhang J, Ma PX, Chen YE. Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin. J Biol Chem. 2012;287(18):14598–605.CrossRefPubMedPubMedCentral
11.
go back to reference Wang X, Hu G, Gao X, Wang Y, Zhang W, Harmon EY, Zhi X, Xu Z, Lennartz MR, Barroso M, et al. The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation. Arterioscler Thromb Vasc Biol. 2012;32(11):2662–9.CrossRefPubMedPubMedCentral Wang X, Hu G, Gao X, Wang Y, Zhang W, Harmon EY, Zhi X, Xu Z, Lennartz MR, Barroso M, et al. The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation. Arterioscler Thromb Vasc Biol. 2012;32(11):2662–9.CrossRefPubMedPubMedCentral
12.
go back to reference Choi HJ, Zhang H, Park H, Choi KS, Lee HW, Agrawal V, Kim YM, Kwon YG. Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun. 2015;6:6943.CrossRefPubMed Choi HJ, Zhang H, Park H, Choi KS, Lee HW, Agrawal V, Kim YM, Kwon YG. Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun. 2015;6:6943.CrossRefPubMed
14.
go back to reference Zheng YZ, Xie MS, Liu GH, Liu A, Jin WE. Effect of Jiawei Buyang Huanwu Decoction on Retinal Hemodynamics of Diabetic Rats. Journal of Shanxi College of Traditional Chinese Medicine. 2013;14:24–7. Zheng YZ, Xie MS, Liu GH, Liu A, Jin WE. Effect of Jiawei Buyang Huanwu Decoction on Retinal Hemodynamics of Diabetic Rats. Journal of Shanxi College of Traditional Chinese Medicine. 2013;14:24–7.
15.
go back to reference Duan H, Huang J, Li W, Tang M. Protective effects of fufang xueshuantong on diabetic retinopathy in rats. Evid Based Complement Alternat Med. 2013;2013:408268.CrossRefPubMedPubMedCentral Duan H, Huang J, Li W, Tang M. Protective effects of fufang xueshuantong on diabetic retinopathy in rats. Evid Based Complement Alternat Med. 2013;2013:408268.CrossRefPubMedPubMedCentral
16.
go back to reference Yuwei X, Junjie Z, Yongquan S, Zhimin L. Protection of Fufang Xueshuantong Capsule Against Retinal Oxidative Damage of Diabetic Rats. J Med Res. 2016;45(1):40–3. Yuwei X, Junjie Z, Yongquan S, Zhimin L. Protection of Fufang Xueshuantong Capsule Against Retinal Oxidative Damage of Diabetic Rats. J Med Res. 2016;45(1):40–3.
17.
go back to reference Jian W, Yu S, Tang M, Duan H, Huang J. A combination of the main constituents of Fufang Xueshuantong Capsules shows protective effects against streptozotocin-induced retinal lesions in rats. J Ethnopharmacol. 2016;182:50–6.CrossRefPubMed Jian W, Yu S, Tang M, Duan H, Huang J. A combination of the main constituents of Fufang Xueshuantong Capsules shows protective effects against streptozotocin-induced retinal lesions in rats. J Ethnopharmacol. 2016;182:50–6.CrossRefPubMed
18.
go back to reference Baydar S, Adapinar B, Kebapci N, Bal C, Topbas S. Colour Doppler ultrasound evaluation of orbital vessels in diabetic retinopathy. Australas Radiol. 2007;51(3):230–5.CrossRefPubMed Baydar S, Adapinar B, Kebapci N, Bal C, Topbas S. Colour Doppler ultrasound evaluation of orbital vessels in diabetic retinopathy. Australas Radiol. 2007;51(3):230–5.CrossRefPubMed
19.
go back to reference Sharma NK, Gardiner TA, Archer DB. A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats. Am J Ophthalmol. 1985;100(1):51–60.CrossRefPubMed Sharma NK, Gardiner TA, Archer DB. A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats. Am J Ophthalmol. 1985;100(1):51–60.CrossRefPubMed
20.
go back to reference Shie JL, Wu G, Wu J, Liu FF, Laham RJ, Oettgen P, Li J. RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. J Biol Chem. 2004;279(24):25010–6.CrossRefPubMed Shie JL, Wu G, Wu J, Liu FF, Laham RJ, Oettgen P, Li J. RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. J Biol Chem. 2004;279(24):25010–6.CrossRefPubMed
21.
go back to reference Zhou Z, Zhu JS, Xu ZP. RNA interference mediated YAP gene silencing inhibits invasion and metastasis of human gastric cancer cell line SGC-7901. Hepato-Gastroenterology. 2011;58(112):2156–61.PubMed Zhou Z, Zhu JS, Xu ZP. RNA interference mediated YAP gene silencing inhibits invasion and metastasis of human gastric cancer cell line SGC-7901. Hepato-Gastroenterology. 2011;58(112):2156–61.PubMed
22.
go back to reference Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11(12):1444–50.CrossRefPubMedPubMedCentral Zhang J, Ji JY, Yu M, Overholtzer M, Smolen GA, Wang R, Brugge JS, Dyson NJ, Haber DA. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009;11(12):1444–50.CrossRefPubMedPubMedCentral
23.
go back to reference Essafi-Benkhadir K, Pouyssegur J, Pages G. Implication of the ERK pathway on the post-transcriptional regulation of VEGF mRNA stability. Methods Mol Biol. 2010;661:451–69.CrossRefPubMed Essafi-Benkhadir K, Pouyssegur J, Pages G. Implication of the ERK pathway on the post-transcriptional regulation of VEGF mRNA stability. Methods Mol Biol. 2010;661:451–69.CrossRefPubMed
24.
go back to reference Curry JM, Eubank TD, Roberts RD, Wang Y, Pore N, Maity A, Marsh CB. M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo. PLoS One. 2008;3(10):e3405.CrossRefPubMedPubMedCentral Curry JM, Eubank TD, Roberts RD, Wang Y, Pore N, Maity A, Marsh CB. M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo. PLoS One. 2008;3(10):e3405.CrossRefPubMedPubMedCentral
25.
go back to reference Michaelis UR, Chavakis E, Kruse C, Jungblut B, Kaluza D, Wandzioch K, Manavski Y, Heide H, Santoni MJ, Potente M, et al. The polarity protein Scrib is essential for directed endothelial cell migration. Circ Res. 2013;112(6):924–34.CrossRefPubMed Michaelis UR, Chavakis E, Kruse C, Jungblut B, Kaluza D, Wandzioch K, Manavski Y, Heide H, Santoni MJ, Potente M, et al. The polarity protein Scrib is essential for directed endothelial cell migration. Circ Res. 2013;112(6):924–34.CrossRefPubMed
26.
go back to reference O'Hayre M, Degese MS, Gutkind JS. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol. 2014;27:126–35.CrossRefPubMedPubMedCentral O'Hayre M, Degese MS, Gutkind JS. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol. 2014;27:126–35.CrossRefPubMedPubMedCentral
27.
go back to reference Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, et al. Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes. Diabetes. 2002;51(1):114–23.CrossRefPubMed Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, et al. Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes. Diabetes. 2002;51(1):114–23.CrossRefPubMed
28.
go back to reference Choi HS, Cho DI, Choi HK, Im SY, Ryu SY, Kim KM. Molecular mechanisms of inhibitory activities of tanshinones on lipopolysaccharide-induced nitric oxide generation in RAW 264.7 cells. Arch Pharm Res. 2004;27(12):1233–7.CrossRefPubMed Choi HS, Cho DI, Choi HK, Im SY, Ryu SY, Kim KM. Molecular mechanisms of inhibitory activities of tanshinones on lipopolysaccharide-induced nitric oxide generation in RAW 264.7 cells. Arch Pharm Res. 2004;27(12):1233–7.CrossRefPubMed
29.
go back to reference Liu XY, Zhou XY, Hou JC, Zhu H, Wang Z, Liu JX, Zheng YQ. Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway. Acta Pharmacol Sin. 2015;36(4):421–8.CrossRefPubMedPubMedCentral Liu XY, Zhou XY, Hou JC, Zhu H, Wang Z, Liu JX, Zheng YQ. Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway. Acta Pharmacol Sin. 2015;36(4):421–8.CrossRefPubMedPubMedCentral
30.
go back to reference Yang BR, Hong SJ, Lee SM, Cong WH, Wan JB, Zhang ZR, Zhang QW, Zhang Y, Wang YT, Lin ZX. Pro-angiogenic activity of notoginsenoside R1 in human umbilical vein endothelial cells in vitro and in a chemical-induced blood vessel loss model of zebrafish in vivo. Chin J Integr Med. 2016;22(6):420–9.CrossRefPubMed Yang BR, Hong SJ, Lee SM, Cong WH, Wan JB, Zhang ZR, Zhang QW, Zhang Y, Wang YT, Lin ZX. Pro-angiogenic activity of notoginsenoside R1 in human umbilical vein endothelial cells in vitro and in a chemical-induced blood vessel loss model of zebrafish in vivo. Chin J Integr Med. 2016;22(6):420–9.CrossRefPubMed
31.
go back to reference Park KS. Aucubin, a naturally occurring iridoid glycoside inhibits TNF-alpha-induced inflammatory responses through suppression of NF-kappaB activation in 3T3-L1 adipocytes. Cytokine. 2013;62(3):407–12.CrossRefPubMed Park KS. Aucubin, a naturally occurring iridoid glycoside inhibits TNF-alpha-induced inflammatory responses through suppression of NF-kappaB activation in 3T3-L1 adipocytes. Cytokine. 2013;62(3):407–12.CrossRefPubMed
Metadata
Title
The Hippo signaling pathway: a potential therapeutic target is reversed by a Chinese patent drug in rats with diabetic retinopathy
Authors
Gai-mei Hao
Tian-tian Lv
Yan Wu
Hong-liang Wang
Wei Xing
Yong Wang
Chun Li
Zi-jian Zhang
Zheng-lin Wang
Wei Wang
Jing Han
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2017
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-017-1678-3

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