腎纖維化是從急性腎損傷(AKI)轉變為慢性腎臟疾病(CKD)的重要特徵。局部缺氧和硬化程度升高是纖維化腎臟的基本特徵。缺氧誘導因子(HIF-1α)是缺氧反應之主要調節分子之一，基於其轉錄活性，Hippo訊息途徑下游之作用蛋白YAP在多種病理生理功能的調節中也有重要作用。在這項研究中，我們專注於缺氧對HIF-1α和YAP信號傳導的影響。給予CoCl2或在1％ O2厭氧箱以模擬缺氧狀況。HIF-1α和YAP核易位的半定量共軛焦成像用於評估其在缺氧條件下的表達和活性。我們觀察到在缺氧條件下，YAP在高細胞密度培養中易位到細胞核中，這表明HIF-1α可能將YAP轉運到細胞核中。此外，我們證明了即使在1小時的CoCl2處理下，YAP仍迅速在細胞核中積累。同時，西方點墨法觀察到的MST1/2和LATS1的磷酸化水平在CoCl2介導的缺氧條件下顯著降低，表明Hippo途徑可能參與了缺氧誘導的YAP核易位。我們進一步排除了三條非HIF-1α依賴性途徑(Src，ERK和AKT途徑)在缺氧條件下基於西方點墨法和免疫螢光染色分析對YAP核易位的影響。此外，我們觀察到儘管ERK1/2途徑在CoCl2介導的缺氧條件下被激活，但Src和AKT途徑卻未被激活。但是，未觀察到ERK1/2的激活與缺氧誘導的YAP核易位有關。在缺氧條件下，在免疫螢光圖像中觀察到HIF-1α和YAP在細胞核中的共定位。此外，免疫沉澱法的結果表明在CoCl2介導的缺氧條件下HIF-1α與YAP之間存在相互作用。透過抑制Madin-Darby犬腎臟上皮細胞（MDCK）中的HIF-1α來評估HIF-1α的位置是否影響YAP核易位。半定量共軛焦圖像顯示在CoCl2介導的缺氧條件下HIF-1α缺失的細胞顯示YAP位在細胞質。根據西方點墨法結果，在CoCl2介導的缺氧條件下ZO-1和E-鈣黏著蛋白的下降以及N-鈣黏著蛋白表達的上升可以證明缺氧在上皮-間質細胞轉換中的作用。總體而言，這些數據表明在缺氧條件下Hippo途徑受到抑制，HIF-1α表達被激活，從而使YAP被HIF-1α轉運入細胞核並促進上皮-間質細胞轉換。描述缺氧條件下HIF-1α和YAP之間的相互作用可能有助於確定預防腎纖維化進展的方法。

Renal fibrosis is an important characteristic of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Local hypoxia and elevated stiffness are constitutive traits of fibrotic kidneys. Hypoxia-inducible factor 1-alpha (HIF-1α) is one of the major mediators of hypoxic response, and the Hippo pathway downstream effector YAP also plays an important role in the regulation of multiple pathophysiological functions based on its transcriptional activity. In this study, we focused on the effect of hypoxia on HIF-1α and YAP signaling. CoCl2 treatment or 1% O2 hypoxia chamber incubation was performed to mimic hypoxic conditions. Semi-quantitative confocal imaging of the nuclear translocation of HIF-1α and YAP was performed to evaluate their expression and activity under hypoxia. We observed that YAP is translocated into the nucleus in a high cell density culture under hypoxic conditions, which indicated that HIF-1α may transport YAP into the nucleus. Furthermore, we demonstrated the rapid accumulation of YAP in the nucleus even after 1 h of CoCl2 treatment. Meanwhile, the levels of MST1/2 and LATS1 phosphorylation, as observed in Western blotting experiments, decreased significantly under CoCl2-mediated hypoxia, suggesting that the Hippo pathway might be involved in the hypoxia-induced nuclear translocation of YAP. We further ruled out the involvement of three non-HIF-1α dependent pathways (Src, ERK, and AKT pathways) in the nuclear translocation of YAP under hypoxic conditions based on Western blotting and immunofluorescence staining analysis. In addition, we observed that while the ERK1/2 pathway was activated under CoCl2-mediated hypoxia, the Src and AKT pathways were not. However, ERK1/2 activation was not observed to be related to the hypoxia-induced nuclear translocation of YAP. The colocalization of HIF-1α and YAP in the nucleus under hypoxic conditions was observed in the immunofluorescence images. In addition, the immunoprecipitation results revealed the interaction between HIF-1α and YAP under CoCl2-mediated hypoxia. HIF-1α depletion was induced in Madin-Darby Canine Kidney (MDCK) cells to evaluate whether the location of HIF-1α affects the nuclear translocation of YAP. Semi-quantification confocal imaging revealed that YAP was localized to the cytoplasm in HIF-1α-depleted cells under CoCl2-mediated hypoxia. Based on the Western blotting results, the reduction in ZO-1 and E-cadherin levels and the increase in N-cadherin levels under CoCl2-mediated hypoxia indicated the role of hypoxia in epithelial-mesenchymal transition (EMT). Collectively, these data suggest that under hypoxic conditions, the Hippo pathway is inhibited and HIF-1α expression is activated, which consequently enables the transport of YAP into the nucleus by HIF-1α and promotes EMT. Describing the interaction between HIF-1α and YAP under hypoxia might help determine methods to prevent the progression of renal fibrosis.

Abbate, M., Zoja, C., Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 2006;17:2974–¬2984.
Anders, H.J., Vielhauer, V., Schlondorff, D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int. 2003;63:401–415.
Basu, S., Totty, N.F., Irwin, M.S., Sudol, M., Downward, J. Akt phosphorylates the Yes–associated protein, YAP, to induce interaction with 14–3–3 and attenuation of p73–mediated apoptosis. Mol. Cell. 2003;11:11–23.
Beitner–Johnson, D., Rust, R.T., Hsieh, T.C., Millhorn, D.E. Hypoxia activates Akt and induces phosphorylation of GSK–3 in PC12 cells. Cell Signal. 2001;13:23–27.
Biernacka, A., Dobaczewski, M., Frangogiannis, N.G. TGF–beta signaling in fibrosis. Growth Factors 2011;29:196–202.
Breyer, M.D., Susztak, K. Developing treatments for chronic kidney disease in the 21st century. Semin. Nephrol. 2016;36:436–447.
Basile, D.P., Bonventre, J.V., Mehta, R., Nangaku, M., Unwin, R., Rosner, M.H., Kellum, J.A., Ronco, C.; ADQI XIII Work Group. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J. Am. Soc. Nephrol. 2016;27:687–697.
Bonventre, J.V. Maladaptive proximal tubule repair: cell cycle arrest. Nephron. Clin. Pract. 2014;127:61–64.
Boor, P., Ostendorf, T., Floege, J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat. Rev. Nephrol. 2010;6:643.
Border, W.A., Noble, N.A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 1994;331:1286–1292.
Cerychova, R, Pavlinkova, G. HIF–1, metabolism, and diabetes in the embryonic and adult heart. Front. Endocrinol. (Lausanne) 2018;9:460.
Chawla, S.L., Bellomo, R., Bihorac, A.L., Goldstein, S., Siew, D.E., Bagshaw, M.S., Bittleman, D., Cruz, D., Endre, Z., Fitzgerald, L.R., Forni, L., Kane–Gill, L.S., Hoste, E., Koyner, J., Liu, D.K., Macedo, E., Mehta, R., Murray, P., Nadim, M., Ostermann, M., Palevsky, M.P., Pannu, N., Rosner, M., Wald, R., Zarbock, A., Ronco C., and Kellum A.J., Acute Disease Quality Initiative Workgroup 16. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat. Rev. Nephrol. 2017;13:241¬–257.
Chou, Y.H., Huang, T.M., Chu, T.S. Novel insights into acute kidney injury–chronic kidney disease continuum and the role of renin–angiotensin system. J. Formos. Med. Assoc. 2017;116:652–659.
Dai, Y., Siemann, D. c–Src is required for hypoxia–induced metastasis–associated functions in prostate cancer cells. Onco. Targets Ther. 2019;12:3519–3529.
Darby, I.A., Hewitson, T.D. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 2016;365:553–562.
Denko, N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 2008;8:705–713.
Deshmane, S.L., Kremlev, S., Amini, S., Sawaya, B.E. Monocyte chemoattractant protein–1 (MCP–1): an overview. J. Interferon Cytokine Res. 2009;29:313–326.
Dobrokhotov, O., Samsonov, M., Sokabe, M., Hirata, H. Mechanoregulation and pathology of YAP/TAZ via Hippo and non–Hippo mechanisms. Clin. Transl. Med. 2018;7:23.
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Digabel, J.L., Forcato, M., Bicciato, S., Elvassore, N., Piccolo, S. Role of YAP/TAZ in mechanotransduction. Nature 2011;474:179–183.
Epstein, A.C., Gleadle, J.M., McNeill L.A., Fine, L.G., Norman, J.T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int. 2008;74:867–872.
Epstein, A.C., Gleadle, J.M., McNeill, L.A., Hewitson, K.S., O'Rourke, J., Mole, D.R., Mukherji, M., Metzen, E., Wilson, M.I., Dhanda, A., Tian, Y.M., Masson, N., Hamilton, D.L., Jaakkola, P., Barstead, R., Hodgkin, J., Maxwell, P.H., Pugh, C.W., Schofield, C.J., Ratcliffe, P.J. C. elegans EGL–9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43–54.
Eddy, A.A., Neilson, E.G. Chronic kidney disease progression. J. Am. Soc. Nephrol. 2006;17:2964–2966.
Ferenbach, D.A., Bonventre, J.V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 2015;11:264–276.
Forino, M., Torregrossa, R., Ceol, M., Murer, L., Della Vella, M., Del Prete, D., D'Angelo, A., Anglani, F. TGFbeta1 induces epithelial–mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture. Int. J. Exp. Pathol. 2006;87:197–208.
Gewin, L.S. Transforming growth factor–beta in the acute kidney injury to chronic kidney disease transition. Nephron. 2019;143:154–157.
Ghayur, A., Margetts, P.J. Transforming growth factor–beta and the glomerular filtration barrier. Kidney Res. Clin. Pract. 2013;32:3–10.
Greenhough, A., Bagley, C., Heesom, K.J., Gurevich, D.B., Gay, D., Bond, M., Collard, T.J., Paraskeva, C., Martin, P., Sansom, O.J., Malik, K., Williams, A.C. Cancer cell adaptation to hypoxia involves a HIF–GPRC5A–YAP axis. EMBO Mol. Med. 2018;10:e8699.
Ghavami, S., Cunnington, R.H., Gupta, S., Yeganeh, B., Filomeno, K.L., Freed, D.H., Chen, S., Kionisch, T., Halayko, A.J., Ambrose, E., Singal, R., Dixon, I.M.C. Autophagy is a regulator of TGF–β1–induced fibrogenesis in primary human atrial myofibroblasts. Cell Death Dis. 2015;6:e1696.
Hemmelgarn, B.R., Clement, F., Manns, B.J., Klarenbach, S., James, M.T., Ravani, P., Pannu, N., Ahmed, S.B., MacRae, J., Scott–Douglas, N., Jindal, K., Quinn, R., Culleton, B.F., Wiebe, N., Krause, R., Thorlacius, L., Tonelli, M. Overview of the Alberta Kidney Disease Network. BMC Nephrol. 2009;10:30.
Hewitson, K.S., McNeill, L.A., Riordan, M.V., Tian, Y.M., Bullock, A.N., Welford, R.W., Elkins, J.M., Oldham, N.J., Bhattacharya, S., Gleadle, J.M. Ratcliffe, P.J., Pugh, C.W., Schofield. C.J. Hypoxia–inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 2002;277:26351–26355.
Halder, G., Johnson, R.L. Hippo signaling: growth control and beyond. Development 2011;138:9–22.
Hartel, F.V., Holl, M., Arshad, M., Aslam, M., Gunduz, D., Weyand, M., Micoogullari, M., Abdallah, Y., Piper, H.M., Noll, T. Transient hypoxia induces ERK–dependent anti–apoptotic cell survival in endothelial cells. Am. J. Physiol. Cell Physiol. 2010;298:C1501–C1509.
Hung, J.J., Yang, M.H., Hsu, H.S., Hsu, W.H., Liu, J.S., Wu, K.J. Prognostic significance of hypoxia–inducible factor–1alpha, TWIST1 and Snail expression in resectable non–small cell lung cancer. Thorax 2009;64:1082–1089.
Imig, J.D., Ryan, M.J. Immune and inflammatory role in renal disease. Compr. Physiol. 2013;3:957–976.
Inda Filho, A.J., Melamed, M.L. Vitamin D and kidney disease: what we know and what we do not know. J. Bras. Nefrol. 2013;35:323–331.
Jia, Y., Li, H.Y., Wang, J., Wang, Y., Zhang, P., Ma, N., Mo, S.J. Phosphorylation of 14–3–3zeta links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis. Oncogenesis 2019;8:31.
Joyner, M.J., Casey, D.P. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol. Rev. 2015;95:549–601.
Ke, Q., Costa, M. Hypoxia–inducible factor–1 (HIF–1). Mol. Pharmacol. 2006;70(5):1469–1480.
Kellum, J.A. Persistent acute kidney injury. Crit. Care. Med. 2015;43:1785–1786.
Kellum, J.A., Sileanu, F.E., Murugan, R., Lucko, N., Shaw, A.D., Clermont, G. Classifying AKI by urine output versus serum creatinine level. J. Am. Soc. Nephrol. 2015;26:2231–2238.
Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for acute kidney injury. Kidney Int. Suppl. 2012;2:1–138.
Kopp. J.B., Factor V.M., Mozes, M., Nagy, P., Sanderson, N., Böttinger, E.P., Klotman, P.E., Thorgeirsson, S.S. Transgenic mice with increased plasma levels of TGF–beta 1 develop progressive renal disease. Lab. Invest. 1996;74:991–1003
Kimura, K., Iwano, M., Higgins, D.F., Yamaguchi, Y., Nakatani, K., Harada, K. Kubo, A., Akai, Y., Rankin, E.B., Neilson, E.G., Haas,e V.H., Saito, Y. Stable expression of HIF–1α in tubular epithelial cells promotes interstitial fibrosis. Am. J. Physiol. Renal Physiol. 2008;295:F1023–F1029.
Kanai, F., Marignani, P.A., Sarbassova, D., Yagi, R., Hall, R.A., Donowitz, M., Hisaminato, A., Fujiwara, T., Ito, Y., Cantley, L.C., Yaffe, M.B.. TAZ: a novel transcriptional co–activator regulated by interactions with 14–3–3 and PDZ domain proteins. EMBO J. 2000;19:6778–6791.
Lamar, J.M., Xiao, Y., Norton, E., Jiang, Z.G., Gerhard, G.M., Kooner, S., Warren, J.S.A., O. Hynes, R. SRC tyrosine kinase activates the YAP/TAZ axis and thereby drives tumor growth and metastasis. J. Biol. Chem. 2019;294:2302–2317.
Li, M., Luan, F., Zhao, Y., Hao, H., Zhou, Y., Han, W., Fu, X. Epithelial–mesenchymal transition: an emerging target in tissue fibrosis. Exp. Biol. Med. (Maywood) 2016;241:1–13.
Liang, M., Yu, M., Xia, R., Song, K., Wang, J., Luo, J., Chen, G., Cheng, J. Yap/Taz deletion in Gli+ cell–derived myofibroblasts attenuates fibrosis. J. Am. Soc. Nephrol. 2017;28:3278–3290.
Liu, M., Ning, X., Li, R., Yang, Z., Yang, X., Sun, S., Qian, Q. Signalling pathways involved in hypoxia–induced renal fibrosis. J. Cell Mol. Med. 2017;21:1248–1259.
Lovisa, S., LeBleu, V.S., Tampe, B., Sugimoto, H., Vadnagara, K., Carstens, J.L., Wu, C.C., Hagos, Y., Burckhardt, B.C., Pentcheva–Hoang T., Nischal, H., Allison, J.P., Zeisberg, M., Kalluri, R. Epithelial–to–mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat. Med. 2015;21:998–1012.
Lovisa, S., Zeisberg, M., Kalluri, R. Partial epithelial–to–mesenchymal transition and other new mechanisms of kidney fibrosis. Trends Endocrinol. Metab. 2016;27:681–695.
LeBleu, V.S., Taduri, G., O’Connell, J., Teng, Y., Cooke, V.G., Woda, C., Sugimoto, H., Kalluri, R. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 2013;19:1047–1055.
Levey, S.A., Coresh, J. Chronic kidney disease. Lancet 2012;379:165–180.
Masoud, G.N., Li, W. HIF–1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B 2015;5:378–389.
Makris, K., Spanou, L. Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin. Biochem. Rev. 2016;37:85–98.
Metzen, E., Zhou, J., Jelkmann, W., Fandrey, J., Brüne, B. Nitric oxide impairs normoxic degradation of HIF–1alpha by inhibition of prolyl hydroxylases. Mol. Biol. Cell 2003;14:3470–3481.
Meran, S., Steadman, R. Fibroblasts and myofibroblasts in renal fibrosis. Int. J. Exp. Pathol. 2011;92:158–167.
Milane, L., Duan, Z., Amiji, M. Role of hypoxia and glycolysis in the development of multi–drug resistance in human tumor cells and the establishment of an orthotopic multi–drug resistant tumor model in nude mice using hypoxic pre–conditioning. Cancer Cell Int. 2011;11:3.
Munger, J.S., Sheppard, D. Cross talk among TGF–beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb. Perspect. Biol. 2011;3:a005017.
Miyajima, A., Chen, J., Lawrence, C., Ledbetter, S., Soslow, R.A., Stern, J., Jha, S., Pigato, J., Lemer, M.L., Poppas, D.P., Vaughan, E.D., Felsen, D. Antibody to transforming growth factor–β ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int. 2000;58:2301–2313.
Nath, K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am. J. Kidney Dis. 1992;20:1–17.
Norman, J.T., Clark, I.M., Garcia, P.L. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 2000;58:2351–2366.
Noguchi, S., Saito, A., Nagase, T. YAP/TAZ signaling as a molecular link between fibrosis and cancer. Int. J. Mol. Sci. 2018;19:3674.
Nogueira, A., Pires, M.J., Oliveira, P.A. Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In Vivo 2017;31:1–22.
Okamoto, A., Sumi, C., Tanaka, H., Kusunoki, M., Iwai, T., Nishi, K., Matsuo, Y., Harada, H., Takenaga, K., Bono, H., Hirota, K. HIF–1–mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine–induced cell death. Sci. Rep. 2017;7:3816.
O'Connor, J.W., Gomez, E.W. Biomechanics of TGFβ–induced epithelial–mesenchymal transition: implications for fibrosis and cancer. Clin. Transl. Med. 2014;3:23.
Plouffe, S.W., Lin, K.C., Moore, J.L., 3rd, Tan, F.E., Ma, S., Ye, Z., Qiu, Y., Ren, B., Guan, K.L. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J. Biol. Chem. 2018;293:11230–11240.
Patiar, S., Harris, A.L. Role of hypoxia–inducible factor–1alpha as a cancer therapy target. Endocr. Relat. Cancer 2006;13:61–75.
Schnaper, H.W. The tubulointerstitial pathophysiology of progressive kidney disease. Adv. Chronic Kidney Dis. 2017;24:107–116.
Schodel, J., Ratcliffe, P.J. Mechanisms of hypoxia signalling: new implications for nephrology. Nat. Rev. Nephrol. 2019;15:641–659.
Shu, S., Wang, Y., Zheng, M., Liu, Z., Cai, J., Tang, C., Dong, Z. Hypoxia and hypoxia–inducible factors in kidney injury and repair. Cells 2019;8:207.
Sharma, K., Ix, J.H., Mathew, A.V., Cho, M., Pflueger, A., Dunn, S.R., Francos, B., Sharma, S., Falkner, B., McGowan, T.A., Donohue, M., Ramachandrarao, S., Xu, R., Fervenza, F.C., Kopp, J.B. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 2011;22:1144–1151.
Strutz, F., Zeisberg, M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J. Am. Soc. Nephrol. 2006;17:2992–2998.
Sun, Y.B., Qu, X., Caruana, G., Li, J. The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation 2016;92:102–107.
Schinner, E., Schramm, A., Kees, F., Hofmann, F., Schlossmann, J. The cyclic GMP–dependent protein kinase Iα supresses kidney fibrosis. Kidney Int. 2013;84:1198–1206.
Semenza, G.L. HIF–1: mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol. 2000;88:1474–1480.
Semenza, G.L. HIF–1 and tumor progression: pathophysiology and therapeutics.Trends Mol. Med. 2002;8:S62–S67.
Seko, Y., Tobe, K., Takahashi, N., Kaburagi, Y., Kadowaki, T., Yazaki, Y. Hypoxia and hypoxia/reoxygenation activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes. Biochem. Biophys. Res. Commun. 1996;226:530–535.
Sharaf El Din, U.A., Salem, M.M., Abdulazim, D.O. Stop chronic kidney disease progression: Time is approaching. World J. Nephrol. 2016;5:258–273.
Tapon, N., Harvey, K.F., Bell, D.W., Wahrer, D.C., Schiripo, T.A., Haber, D., Hariharan, I.K. Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 2002;110:467–478.
Vaidya, V.S., Ferguson, M.A., Bonventre, J.V. Biomarkers of acute kidney injury. Annu. Rev. Pharmacol. Toxicol. 2008;48:463–493.
Vallon, V., Komers, R. Pathophysiology of the diabetic kidney. Compr. Physiol. 2011;1:1175–1232.
Wang, G.L., Jiang, B.H., Rue, E.A., Semenza, G.L. Hypoxia–inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA. 1995;92:5510–5514.
Wang, X., Hu, G., Gao, X., Wang, Y., Zhang, W., Harmon, E.Y., Zhi, X., Xu, Z., Lennartz, M.R., Barroso, M., Trebak, M., Chen, C., Zhou, J. 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;32:2662–2669.
Wang, Y., Xu, X., Magli,c D., Dill, M.T., Mojumdar, K., Ng, P.K., Jeong, K.J., Tsang, Y.H., Moreno, D., Bhavana, V.H., Peng, X., Ge, Z., Chen, H., Li, J., Chen, Z., Zhang, H., Han, L., Du, D., Creighton, C.J., Mills, G.B.; Cancer Genome Atlas Research Network, Camargo, F., Liang, H. Comprehensive molecular characterization of the Hippo signaling pathway in cancer. Cell Rep. 2018;25:1304–1317.
Xu, C., Wang, L., Zhang, Y., Li, W., Li, J., Wang, Y., Meng, C., Qin, J., Zheng, Z.H., Lan, H.Y., Mak, K.K., Huang, Y., Xia, Y. Tubule–specific Mst1/2 deficiency induces CKD via YAP and non–YAP mechanisms. J. Am. Soc. Nephrol. 2020;31:946–961.
Xu, J., Li, P.X., Wu, J., Gao, Y.J., Yin, M.X., Lin, Y., Yang, M., Chen, D.P., Sun, H.P., Liu, Z.B., Gu, X.C., Huang, H.L., Fu, L.L., Hu, H.M., He, L.L., Wu, W.Q., Fei, Z.L., Ji, H.B., Zhang, L., Mei, C.L. Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector. Clin. Sci. (Lond) 2016;130:349–363.
Xie, L., Law, B.K., Chytil, A.M., Brown, K.A., Askre, M.E., Moses, H.L. Activation of the Erk pathway is required for TGF–β1–induced EMT in vitro. Neoplasia 2004;6:603–610.
Xiang, L., Gilkes, D.M., Hu, H., Luo, W., Bullen, J.W., Liang, H., Semenza, G.L. HIF–1α and TAZ serve as reciprocal co–activators in human breast cancer cells. Oncotarget 2015;6:11768–11778.
Yeo, C.D., Kang, N., Choi, S.Y., Kim, B.N., Park, C.K., Kim, J.W., Kim, Y.K., Kim, S.J. The role of hypoxia on the acquisition of epithelial–mesenchymal transition and cancer stemness: a possible link to epigenetic regulation. Korean J. Intern. Med. 2017;32:589–599.
Yimlamai, D., Christodoulou, C., Galli, G.G., Yanger, K., Pepe–Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B.Z., Camargo, F.D. Hippo pathway activity influences liver cell fate. Cell 2014;157:1324–1338.
Yu, F.X., Guan, K.L. The Hippo pathway: regulators and regulations. Genes Dev. 2013;27:355–371.
You, B., Yang, Y.L., Xu, Z., Dai, Y., Liu, S., Mao, J.H., Tetsu, O., Li, H., Jablons, D.M., You, L. Inhibition of ERK1/2 down–regulates the Hippo/YAP signaling pathway in human NSCLC cells. Oncotarget 2015;6:4357–4368.
Zhang, X., Li, Y., Ma, Y., Yang, L., Wang, T., Meng, X., Zong, Z., Sun, X., Hua, X., Li, H. Yes–associated protein (YAP) binds to HIF–1alpha and sustains HIF–1alpha protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress. J. Exp. Clin. Cancer Res. 2018;37:216.
Zhou, D., Liu, Y. Renal fibrosis in 2015: Understanding the mechanisms of kidney fibrosis. Nat. Rev. Nephrol. 2016;12:68–70.
Zeisberg, M., Hanai, J.I., Sugimoto, H., Mammoto, T., Charytan, D., Strutz, F., Kalluri, R. BMP–7 counteracts TGF–β1–induced epithelial–to–mesenchymal transition and reverses chronic renal injury. Nat. Med. 2003;9:964–968.