Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury
Abstract
:1. Introduction
2. Results
2.1. Construction of mTOR/STAT3 Synthetic ODNs
2.2. mTOR/STAT3 Synthetic ODN Attenuated Morphological Change and Improved Kidney Function in UUO Kidney
2.3. mTOR/STAT3 Synthetic ODN Attenuates UUO-Induced Kidney Tubular Injury
2.4. mTOR/STAT3 Synthetic ODN Inhibited UUO-Induced Kidney Inflammation and Immune Cell Infiltration
2.5. mTOR/STAT3 Synthetic ODN Attenuates UUO-Induced Kidney Damage
2.6. mTOR/STAT3 Synthetic ODN Inhibited UUO-Induced Tubular Cell Apoptosis
3. Discussion
4. Materials and Methods
4.1. Construction of Synthetic ODNs
4.2. Animal Model and Transfection of ODN
4.3. Creatinine and Blood Urea Nitrogen
4.4. Histological Analysis
4.5. Immunohistochemical (IHC) Staining
4.6. Terminal Deoxyuncleotidyl Transferase-Mediated Digoxigenin-Deoxyuridine Nick-End Labeling (TUNEL) Staining and Confocal Microsocpy
4.7. Western Blot Analysis
4.8. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
- Jha, V.; Garcia-Garcia, G.; Iseki, K.; Li, Z.; Naicker, S.; Plattner, B.; Saran, R.; Wang, A.Y.; Yang, C.W. Chronic kidney disease: Global dimension and perspectives. Lancet 2013, 382, 260–272. [Google Scholar] [CrossRef]
- Remuzzi, G.; Bertani, T. Pathophysiology of progressive nephropathies. N. Engl. J. Med. 1998, 339, 1448–1456. [Google Scholar] [CrossRef] [PubMed]
- Xie, H.; Xue, J.D.; Chao, F.; Jin, Y.F.; Fu, Q. Long non-coding RNA-H19 antagonism protects against renal fibrosis. Oncotarget 2016, 7, 51473–51481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boelens, M.C.; Wu, T.J.; Nabet, B.Y.; Xu, B.; Qiu, Y.; Yoon, T.; Azzam, D.J.; Twyman-Saint Victor, C.; Wiemann, B.Z.; Ishwaran, H.; et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 2014, 159, 499–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kawaoka, K.; Doi, S.; Nakashima, A.; Yamada, K.; Ueno, T.; Doi, T.; Masaki, T. Valproic acid attenuates renal fibrosis through the induction of autophagy. Clin. Exp. Nephrol. 2017, 21, 771–780. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bodi, I.; Kimmel, P.L.; Abraham, A.A.; Svetkey, L.P.; Klotman, P.E.; Kopp, J.B. Renal TGF-beta in HIV-associated kidney diseases. Kidney Int. 1997, 51, 1568–1577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xiao, X.; Yuan, Q.; Chen, Y.; Huang, Z.; Fang, X.; Zhang, H.; Peng, L.; Xiao, P. LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis. J. Cell. Physiol. 2019, 234, 9130–9143. [Google Scholar] [CrossRef]
- Klionsky, D.J. Autophagy: From phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 2007, 8, 931–937. [Google Scholar] [CrossRef]
- Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42. [Google Scholar] [CrossRef] [Green Version]
- Hartleben, B.; Godel, M.; Meyer-Schwesinger, C.; Liu, S.; Ulrich, T.; Kobler, S.; Wiech, T.; Grahammer, F.; Arnold, S.J.; Lindenmeyer, M.T.; et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Investig. 2010, 120, 1084–1096. [Google Scholar] [CrossRef] [Green Version]
- Kim, W.Y.; Nam, S.A.; Song, H.C.; Ko, J.S.; Park, S.H.; Kim, H.L.; Choi, E.J.; Kim, Y.S.; Kim, J.; Kim, Y.K. The role of autophagy in unilateral ureteral obstruction rat model. Nephrology 2012, 17, 148–159. [Google Scholar] [CrossRef] [PubMed]
- Livingston, M.J.; Ding, H.F.; Huang, S.; Hill, J.A.; Yin, X.M.; Dong, Z. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy 2016, 12, 976–998. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, R.J.; Lee, Y.H.; Yeh, Y.L.; Wu, W.S.; Ho, C.T.; Li, C.Y.; Wang, B.J.; Wang, Y.J. Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases. J. Food Drug Anal. 2017, 25, 125–133. [Google Scholar] [CrossRef] [PubMed]
- Zhou, H.; Huang, B.; Du, J.; Wang, L. Role of the JAK2/STAT pathway and losartan in human glomerular mesangial cell senescence. Mol. Med. Rep. 2010, 3, 393–398. [Google Scholar]
- Cuervo, A.M. Autophagy and aging: Keeping that old broom working. Trends Genet. 2008, 24, 604–612. [Google Scholar] [CrossRef] [Green Version]
- Yang, S.; Sun, D.; Wang, L.; Wang, X.; Shi, M.; Jiang, X.; Gao, X. The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells. Cell. Signal. 2019, 53, 327–338. [Google Scholar] [CrossRef] [PubMed]
- Lenoir, O.; Tharaux, P.L.; Huber, T.B. Autophagy in kidney disease and aging: Lessons from rodent models. Kidney Int. 2016, 90, 950–964. [Google Scholar] [CrossRef] [Green Version]
- Kimura, T.; Isaka, Y.; Yoshimori, T. Autophagy and kidney inflammation. Autophagy 2017, 13, 997–1003. [Google Scholar] [CrossRef]
- Ding, Y.; Kim, S.; Lee, S.Y.; Koo, J.K.; Wang, Z.; Choi, M.E. Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 2014, 25, 2835–2846. [Google Scholar] [CrossRef] [Green Version]
- Kim, S.I.; Na, H.J.; Ding, Y.; Wang, Z.; Lee, S.J.; Choi, M.E. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J. Biol. Chem. 2012, 287, 11677–11688. [Google Scholar] [CrossRef] [Green Version]
- Gong, J.; Zhan, H.; Li, Y.; Zhang, W.; Jin, J.; He, Q. Kruppellike factor 4 ameliorates diabetic kidney disease by activating autophagy via the mTOR pathway. Mol. Med. Rep. 2019, 20, 3240–3248. [Google Scholar] [PubMed] [Green Version]
- Liu, L.; Yang, L.; Chang, B.; Zhang, J.; Guo, Y.; Yang, X. The protective effects of rapamycin on cell autophagy in the renal tissues of rats with diabetic nephropathy via mTOR-S6K1-LC3II signaling pathway. Ren. Fail. 2018, 40, 492–497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perillo, B.; Sasso, A.; Abbondanza, C.; Palumbo, G. 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol. Cell. Biol. 2000, 20, 2890–2901. [Google Scholar] [CrossRef] [Green Version]
- Alas, S.; Bonavida, B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res. 2001, 61, 5137–5144. [Google Scholar] [PubMed]
- Sepulveda, P.; Encabo, A.; Carbonell-Uberos, F.; Minana, M.D. BCL-2 expression is mainly regulated by JAK/STAT3 pathway in human CD34+ hematopoietic cells. Cell Death Differ. 2007, 14, 378–380. [Google Scholar] [CrossRef] [PubMed]
- Bowman, T.; Garcia, R.; Turkson, J.; Jove, R. STATs in oncogenesis. Oncogene 2000, 19, 2474–2488. [Google Scholar] [CrossRef] [Green Version]
- Feng, Y.; Ke, C.; Tang, Q.; Dong, H.; Zheng, X.; Lin, W.; Ke, J.; Huang, J.; Yeung, S.C.; Zhang, H. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014, 5, e1088. [Google Scholar] [CrossRef]
- Cuervo, A.M.; Bergamini, E.; Brunk, U.T.; Droge, W.; Ffrench, M.; Terman, A. Autophagy and aging: The importance of maintaining “clean” cells. Autophagy 2005, 1, 131–140. [Google Scholar] [CrossRef] [Green Version]
- Chevalier, R.L.; Forbes, M.S.; Thornhill, B.A. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int. 2009, 75, 1145–1152. [Google Scholar] [CrossRef] [Green Version]
- Li, L.; Zepeda-Orozco, D.; Black, R.; Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 2010, 176, 1767–1778. [Google Scholar] [CrossRef] [Green Version]
- Kim, J.Y.; An, H.J.; Kim, W.H.; Gwon, M.G.; Gu, H.; Park, Y.Y.; Park, K.K. Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-beta1 and Smad in an Animal Model of Liver Cirrhosis. Mol. Ther. Nucleic Acids 2017, 8, 250–263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, K.H.; Lee, E.S.; Cha, S.H.; Park, J.H.; Park, J.S.; Chang, Y.C.; Park, K.K. Transcriptional regulation of NF-kappaB by ring type decoy oligodeoxynucleotide in an animal model of nephropathy. Exp. Mol. Pathol. 2009, 86, 114–120. [Google Scholar] [CrossRef] [PubMed]
- Lee, W.R.; Kim, K.H.; An, H.J.; Park, Y.Y.; Kim, K.S.; Lee, C.K.; Min, B.K.; Park, K.K. Effects of chimeric decoy oligodeoxynucleotide in the regulation of transcription factors NF-kappaB and Sp1 in an animal model of atherosclerosis. Basic Clin. Pharmacol. Toxicol. 2013, 112, 236–243. [Google Scholar] [CrossRef] [PubMed]
- Yuan, H.F.; Huang, H.; Li, X.Y.; Guo, W.; Xing, W.; Sun, Z.Y.; Liang, H.P.; Yu, J.; Chen, D.F.; Wang, Z.G.; et al. A dual AP-1 and SMAD decoy ODN suppresses tissue fibrosis and scarring in mice. J. Investig. Dermatol. 2013, 133, 1080–1087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, Y.; Shiou, S.R.; Guo, Y.; Lu, L.; Westerhoff, M.; Sun, J.; Petrof, E.O.; Claud, E.C. Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis. PLoS ONE 2013, 8, e69620. [Google Scholar] [CrossRef] [Green Version]
- Okamura, D.M.; Pasichnyk, K.; Lopez-Guisa, J.M.; Collins, S.; Hsu, D.K.; Liu, F.T.; Eddy, A.A. Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis. Am. J. Physiol. Renal Physiol. 2011, 300, F245–F253. [Google Scholar] [CrossRef] [Green Version]
- Levine, B.; Klionsky, D.J. Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker’s yeast fuel advances in biomedical research. Proc. Natl. Acad. Sci. USA 2017, 114, 201–205. [Google Scholar] [CrossRef] [Green Version]
- Ravanan, P.; Srikumar, I.F.; Talwar, P. Autophagy: The spotlight for cellular stress responses. Life Sci. 2017, 188, 53–67. [Google Scholar] [CrossRef]
- Zhu, L.; Yuan, Y.; Yuan, L.; Li, L.; Liu, F.; Liu, J.; Chen, Y.; Lu, Y.; Cheng, J. Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Theranostics 2020, 10, 5829–5844. [Google Scholar] [CrossRef]
- Bian, A.; Shi, M.; Flores, B.; Gillings, N.; Li, P.; Yan, S.X.; Levine, B.; Xing, C.; Hu, M.C. Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice. PLoS ONE 2017, 12, e0181848. [Google Scholar] [CrossRef] [Green Version]
- Du, C.; Zhang, T.; Xiao, X.; Shi, Y.; Duan, H.; Ren, Y. Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Biochem. J. 2017, 474, 2733–2747. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Nartiss, Y.; Steipe, B.; Mcquibban, G.A.; Kim, P.K. ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy 2012, 8, 1462–1476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, T.A.; Wu, V.C.; Wang, C.Y. Autophagy in Chronic Kidney Diseases. Cells 2019, 8, 61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, G.; Yue, F.; Huang, H.; He, Y.; Li, X.; Zhao, H.; Su, Z.; Jiang, X.; Li, W.; Zou, J.; et al. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging. 2016, 8, 977–985. [Google Scholar] [CrossRef] [Green Version]
- Peng, X.; Wang, Y.; Li, H.; Fan, J.; Shen, J.; Yu, X.; Zhou, Y.; Mao, H. ATG5-mediated autophagy suppresses NF-kappaB signaling to limit epithelial inflammatory response to kidney injury. Cell Death Dis. 2019, 10, 253. [Google Scholar] [CrossRef] [Green Version]
- Velentzas, P.D.; Velentzas, A.D.; Mpakou, V.E.; Antonelou, M.H.; Margaritis, L.H.; Papassideri, I.S.; Stravopodis, D.J. Detrimental effects of proteasome inhibition activity in Drosophila melanogaster: Implication of ER stress, autophagy, and apoptosis. Cell Biol. Toxicol. 2013, 29, 13–37. [Google Scholar] [CrossRef]
- Han, K.; Zhou, H.; Pfeifer, U. Inhibition and restimulation by insulin of cellular autophagy in distal tubular cells of the kidney in early diabetic rats. Kidney Blood Press. Res. 1997, 20, 258–263. [Google Scholar] [CrossRef]
- Kaushal, G.P.; Chandrashekar, K.; Juncos, L.A.; Shah, S.V. Autophagy Function and Regulation in Kidney Disease. Biomolecules 2020, 10, 100. [Google Scholar] [CrossRef] [Green Version]
- Mei, S.; Livingston, M.; Hao, J.; Li, L.; Mei, C.; Dong, Z. Autophagy is activated to protect against endotoxic acute kidney injury. Sci. Rep. 2016, 6, 22171. [Google Scholar] [CrossRef]
- Livingston, M.J.; Dong, Z. Autophagy in acute kidney injury. Semin. Nephrol. 2014, 34, 17–26. [Google Scholar] [CrossRef] [Green Version]
- Xu, X.; Pan, J.; Li, H.; Li, X.; Fang, F.; Wu, D.; Zhou, Y.; Zheng, P.; Xiong, L.; Zhang, D. Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-delta. FASEB J. 2019, 33, 4513–4524. [Google Scholar] [CrossRef] [PubMed]
- Kaushal, G.P.; Shah, S.V. Autophagy in acute kidney injury. Kidney Int. 2016, 89, 779–791. [Google Scholar] [CrossRef] [Green Version]
- Bao, J.; Shi, Y.; Tao, M.; Liu, N.; Zhuang, S.; Yuan, W. Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy. Clin. Sci. 2018, 132, 2299–2322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, S.; Hartleben, B.; Kretz, O.; Wiech, T.; Igarashi, P.; Mizushima, N.; Walz, G.; Huber, T.B. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 2012, 8, 826–837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jiang, M.; Wei, Q.; Dong, G.; Komatsu, M.; Su, Y.; Dong, Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 2012, 82, 1271–1283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kimura, T.; Takabatake, Y.; Takahashi, A.; Kaimori, J.Y.; Matsui, I.; Namba, T.; Kitamura, H.; Niimura, F.; Matsusaka, T.; Soga, T.; et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 2011, 22, 902–913. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, T.; Takabatake, Y.; Kimura, T.; Takahashi, A.; Namba, T.; Matsuda, J.; Minami, S.; Kaimori, J.Y.; Matsui, I.; Kitamura, H.; et al. Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 2016, 12, 801–813. [Google Scholar] [CrossRef] [Green Version]
- Li, L.; Xiao, T.; Li, F.; Li, Y.; Zeng, O.; Liu, M.; Liang, B.; Li, Z.; Chu, C.; Yang, J. Hydrogen sulfide reduced renal tissue fibrosis by regulating autophagy in diabetic rats. Mol. Med. Rep. 2017, 16, 1715–1722. [Google Scholar] [CrossRef] [Green Version]
- Mizushima, N.; Levine, B.; Cuervo, A.M.; Klionsky, D.J. Autophagy fights disease through cellular self-digestion. Nature 2008, 451, 1069–1075. [Google Scholar] [CrossRef] [Green Version]
- Kabeya, Y.; Mizushima, N.; Yamamoto, A.; Oshitani-Okamoto, S.; Ohsumi, Y.; Yoshimori, T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J. Cell Sci. 2004, 117, 2805–2812. [Google Scholar] [CrossRef] [Green Version]
- Tian, F.; Wang, Z.; He, J.; Zhang, Z.; Tan, N. 4-Octyl itaconate protects against renal fibrosis via inhibiting TGF-beta/Smad pathway, autophagy and reducing generation of reactive oxygen species. Eur. J. Pharmacol. 2020, 873, 172989. [Google Scholar] [CrossRef] [PubMed]
- Djavaheri-Mergny, M.; Maiuri, M.C.; Kroemer, G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 2010, 29, 1717–1719. [Google Scholar] [CrossRef] [PubMed]
- Deng, X.S.; Wang, S.; Deng, A.; Liu, B.; Edgerton, S.M.; Lind, S.E.; Wahdan-Alaswad, R.; Thor, A.D. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle 2012, 11, 367–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pattingre, S.; Tassa, A.; Qu, X.; Garuti, R.; Liang, X.H.; Mizushima, N.; Packer, M.; Schneider, M.D.; Levine, B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005, 122, 927–939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, Y.; Ruan, S.; Wu, X.; Chen, H.; Zheng, K.; Fu, B. Autophagy and apoptosis in tubular cells following unilateral ureteral obstruction are associated with mitochondrial oxidative stress. Int. J. Mol. Med. 2013, 31, 628–636. [Google Scholar] [CrossRef] [PubMed]
- Robert, G.; Gastaldi, C.; Puissant, A.; Hamouda, A.; Jacquel, A.; Dufies, M.; Belhacene, N.; Colosetti, P.; Reed, J.C.; Auberger, P.; et al. The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death. Autophagy 2012, 8, 637–649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, H.; Kong, X.; Kang, J.; Su, J.; Li, Y.; Zhong, J.; Sun, L. Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol. Sci. 2009, 110, 376–388. [Google Scholar] [CrossRef]
- Wang, X.; Tao, Y.; Huang, Y.; Zhan, K.; Xue, M.; Wang, Y.; Ruan, D.; Liang, Y.; Huang, X.; Lin, J.; et al. Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1. J. Cell. Mol. Med. 2017, 21, 3420–3434. [Google Scholar] [CrossRef]
- Wei, J.; Jiang, H.; Gao, H.; Wang, G. Blocking Mammalian Target of Rapamycin (mTOR) Attenuates HIF-1alpha Pathways Engaged-Vascular Endothelial Growth Factor (VEGF) in Diabetic Retinopathy. Cell. Physiol. Biochem. 2016, 40, 1570–1577. [Google Scholar] [CrossRef]
- Li, W.; Zhang, P.L. Up-regulated mTOR pathway indicates active disease in both human native and transplant kidneys. Ann. Clin. Lab. Sci. 2013, 43, 378–388. [Google Scholar]
- Zhong, Z.; Wen, Z.; Darnell, J.E., Jr. Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994, 264, 95–98. [Google Scholar] [CrossRef]
- Hunter, C.A.; Jones, S.A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 2015, 16, 448–457. [Google Scholar] [CrossRef] [PubMed]
- Yan, B.; Wei, J.J.; Yuan, Y.; Sun, R.; Li, D.; Luo, J.; Liao, S.J.; Zhou, Y.H.; Shu, Y.; Wang, Q.; et al. IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. J. Immunol. 2013, 190, 5882–5893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, H.; Pardoll, D.; Jove, R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 2009, 9, 798–809. [Google Scholar] [CrossRef] [PubMed]
- You, L.; Wang, Z.; Li, H.; Shou, J.; Jing, Z.; Xie, J.; Sui, X.; Pan, H.; Han, W. The role of STAT3 in autophagy. Autophagy 2015, 11, 729–739. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kroemer, G.; Marino, G.; Levine, B. Autophagy and the integrated stress response. Mol. Cell 2010, 40, 280–293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, H.; Chen, L.; Li, J.J.; Zhou, Q.; Huang, A.; Liu, W.W.; Wang, K.; Gao, L.; Qi, S.T.; Lu, Y.T. miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway. J. Hematol. Oncol. 2018, 11, 70. [Google Scholar] [CrossRef] [Green Version]
- You, L.; Shou, J.; Deng, D.; Jiang, L.; Jing, Z.; Yao, J.; Li, H.; Xie, J.; Wang, Z.; Pan, Q.; et al. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines. Oncotarget 2015, 6, 40268–40282. [Google Scholar] [CrossRef] [Green Version]
- Zhong, L.X.; Zhang, Y.; Wu, M.L.; Liu, Y.N.; Zhang, P.; Chen, X.Y.; Kong, Q.Y.; Liu, J.; Li, H. Resveratrol and STAT inhibitor enhance autophagy in ovarian cancer cells. Cell Death Discov. 2016, 2, 15071. [Google Scholar] [CrossRef]
- Yokoyama, T.; Kondo, Y.; Kondo, S. Roles of mTOR and STAT3 in autophagy induced by telomere 3’ overhang-specific DNA oligonucleotides. Autophagy 2007, 3, 496–498. [Google Scholar] [CrossRef] [Green Version]
- Koesters, R.; Kaissling, B.; Lehir, M.; Picard, N.; Theilig, F.; Gebhardt, R.; Glick, A.B.; Hahnel, B.; Hosser, H.; Grone, H.J.; et al. Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am. J. Pathol. 2010, 177, 632–643. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.H.; Park, K.K. Small RNA- and DNA-based gene therapy for the treatment of liver cirrhosis, where we are? World J. Gastroenterol. 2014, 20, 14696–14705. [Google Scholar] [CrossRef] [PubMed]
- Sepp-Lorenzino, L.; Ruddy, M. Challenges and opportunities for local and systemic delivery of siRNA and antisense oligonucleotides. Clin. Pharmacol. Ther. 2008, 84, 628–632. [Google Scholar] [CrossRef]
- Mann, M.J.; Dzau, V.J. Therapeutic applications of transcription factor decoy oligonucleotides. J. Clin. Investig. 2000, 106, 1071–1075. [Google Scholar] [CrossRef] [PubMed]
- Gwon, M.G.; An, H.J.; Kim, J.Y.; Kim, W.H.; Gu, H.; Kim, H.J.; Leem, J.; Jung, H.J.; Park, K.K. Anti-fibrotic effects of synthetic TGF-beta1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial-mesenchymal transitions. FASEB J. 2020, 34, 333–349. [Google Scholar] [CrossRef] [Green Version]
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Jung, H.J.; An, H.-J.; Gwon, M.-G.; Gu, H.; Bae, S.; Lee, S.-J.; Kim, Y.-A.; Leem, J.; Park, K.-K. Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury. Molecules 2022, 27, 766. https://doi.org/10.3390/molecules27030766
Jung HJ, An H-J, Gwon M-G, Gu H, Bae S, Lee S-J, Kim Y-A, Leem J, Park K-K. Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury. Molecules. 2022; 27(3):766. https://doi.org/10.3390/molecules27030766
Chicago/Turabian StyleJung, Hyun Jin, Hyun-Jin An, Mi-Gyeong Gwon, Hyemin Gu, Seongjae Bae, Sun-Jae Lee, Young-Ah Kim, Jaechan Leem, and Kwan-Kyu Park. 2022. "Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury" Molecules 27, no. 3: 766. https://doi.org/10.3390/molecules27030766
APA StyleJung, H. J., An, H. -J., Gwon, M. -G., Gu, H., Bae, S., Lee, S. -J., Kim, Y. -A., Leem, J., & Park, K. -K. (2022). Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury. Molecules, 27(3), 766. https://doi.org/10.3390/molecules27030766