Login Register Cart 0
Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Mesenchymal Stem Cell-conditioned Medium Protecting Renal Tubular Epithelial Cells by Inhibiting Hypoxia-inducible Factor-1α and Nuclear Receptor Coactivator-1

Author(s): Chunling Liao, Yiping Liu, Yongda Lin, Jiali Wang, Tianbiao Zhou* and Wenjuan Weng*

Volume 19, Issue 10, 2024

Published on: 04 October, 2023

Page: [1369 - 1381] Pages: 13

DOI: 10.2174/011574888X247652230928064627

Price: $65

Abstract

Background: Acute kidney injury (AKI) is characterized by inflammatory infiltration and damage and death of renal tubular epithelial cells (RTECs), in which hypoxia plays an important role. Deferoxamine (DFO) is a well-accepted chemical hypoxia-mimetic agent. Mesenchymal stem cell-conditioned medium (MSC-CM) can reduce local inflammation and repair tissue. In this study, we explored the effect and molecular mechanism of MSC-CM-mediated protection of RTECs under DFO-induced hypoxia.

Methods: Rat renal proximal tubule NRK-52E cells were treated with different concentrations of DFO for 24 hours, followed by evaluation of RTEC injury, using a Cell Counting Kit-8 (CCK-8) to detect cell viability and western blotting to evaluate the expression of transforming growth factor- beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), and hypoxia-inducible factor-1 alpha (HIF-1α) in NRK-52E cells. Then, three groups of NRK-52E cells were used in experiments, including normal control (NC), 25 μM DFO, and 25 μM DFO + MSC-CM. MSC-CM was obtained from the human umbilical cord. MSC-CM was used to culture cells for 12 hours before DFO treatment, then fresh MSC-CM and 25 μM DFO were added, and cells were cultured for another 24 hours before analysis.

Results: Western blotting and cellular immunofluorescence staining showed culture of NRK-52E cells in 25 μM DFO for 24 hours induced HIF-1α and nuclear receptor coactivator-1 (NCoA-1), simulating hypoxia. MSC-CM could inhibit the DFO-induced up-regulation of α-SMA, TGF-β1, HIF-1α and NCoA-1.

Conclusion: Our results suggest that MSC-CM has a protective effect on RTECs by down-regulating HIF-1α and NCoA-1, which may be the harmful factors in renal injury.

« Previous Next »
[1]
Jamadar, A.; Rao, R. Glycogen synthase kinase-3 signaling in acute kidney injury. Nephron J., 2020, 144(12), 609-612.
[http://dx.doi.org/10.1159/000509354] [PMID: 32726778]
[2]
Wang, Y.; Zhu, J.; Liu, Z.; Shu, S.; Fu, Y.; Liu, Y.; Cai, J.; Tang, C.; Liu, Y.; Yin, X.; Dong, Z. The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox Biol., 2021, 38, 101767.
[http://dx.doi.org/10.1016/j.redox.2020.101767] [PMID: 33137712]
[3]
Liu, Z.; Wang, Y.; Shu, S.; Cai, J.; Tang, C.; Dong, Z. Non-coding RNAs in kidney injury and repair. Am. J. Physiol. Cell Physiol., 2019, 317(2), C177-C188.
[http://dx.doi.org/10.1152/ajpcell.00048.2019] [PMID: 30969781]
[4]
Zhang, H.; Xu, R.; Wang, Z. Contribution of oxidative stress to HIF-1-mediated profibrotic changes during the kidney damage. Oxid. Med. Cell. Longev., 2021, 2021, 1-8.
[http://dx.doi.org/10.1155/2021/6114132] [PMID: 34712385]
[5]
Hosohata, K.; Jin, D.; Takai, S.; Glaucocalyxin, A. Glaucocalyxin A ameliorates hypoxia/reoxygenation-induced injury in human renal proximal tubular epithelial cell line HK-2 cells. Int. J. Mol. Sci., 2021, 23(1), 446.
[http://dx.doi.org/10.3390/ijms23010446] [PMID: 35008870]
[6]
Tiwari, R.; Kapitsinou, P.P. Role of endothelial prolyl-4-hydroxylase domain protein/hypoxia-inducible factor axis in acute kidney injury. Nephron, 2021, 46, 1-6.
[PMID: 34515168]
[7]
Levey, A.S.; James, M.T. Acute kidney injury. Ann. Intern. Med., 2017, 167(9), ITC66-ITC80.
[http://dx.doi.org/10.7326/AITC201711070] [PMID: 29114754]
[8]
Zilberman-Itskovich, S.; Abu-Hamad, R.; Zarura, R.; Sova, M.; Hachmo, Y.; Stark, M.; Neuman, S.; Slavin, S.; Efrati, S. Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury. PLoS One, 2019, 14(9), e0222354.
[http://dx.doi.org/10.1371/journal.pone.0222354] [PMID: 31513644]
[9]
Lelek, J.; Zuba-Surma, E.K. Perspectives for future use of extracellular vesicles from umbilical cord- and adipose tissue-derived mesenchymal stem/stromal cells in regenerative therapies-synthetic review. Int. J. Mol. Sci., 2020, 21(3), 799.
[http://dx.doi.org/10.3390/ijms21030799] [PMID: 31991836]
[10]
Herberts, C.A.; Kwa, M.S.G.; Hermsen, H.P.H. Risk factors in the development of stem cell therapy. J. Transl. Med., 2011, 9(1), 29.
[http://dx.doi.org/10.1186/1479-5876-9-29] [PMID: 21418664]
[11]
Wang, S.; Tong, M.; Hu, S.; Chen, X. The bioactive substance secreted by MSC retards mouse aortic vascular smooth muscle cells calcification. BioMed Res. Int., 2018, 2018, 1-10.
[http://dx.doi.org/10.1155/2018/6053567] [PMID: 29967775]
[12]
Nagaishi, K.; Mizue, Y.; Chikenji, T.; Otani, M.; Nakano, M.; Konari, N.; Fujimiya, M. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci. Rep., 2016, 6(1), 34842.
[http://dx.doi.org/10.1038/srep34842] [PMID: 27721418]
[13]
Harrell, C.R.; Jankovic, M.G.; Fellabaum, C.; Volarevic, A.; Djonov, V.; Arsenijevic, A.; Volarevic, V. Molecular mechanisms responsible for anti-inflammatory and immunosuppressive effects of mesenchymal stem cell-derived factors. Adv. Exp. Med. Biol., 2018, 1084, 187-206.
[http://dx.doi.org/10.1007/5584_2018_306] [PMID: 31175638]
[14]
Da Silva, A.F.; Silva, K.; Reis, L.A.; Teixeira, V.P.C.; Schor, N. Bone marrow-derived mesenchymal stem cells and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction. Cell Transplant., 2015, 24(12), 2657-2666.
[http://dx.doi.org/10.3727/096368915X687534] [PMID: 25695732]
[15]
van Koppen, A.; Joles, J.A.; van Balkom, B.W.M.; Lim, S.K.; de Kleijn, D.; Giles, R.H.; Verhaar, M.C. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One, 2012, 7(6), e38746.
[http://dx.doi.org/10.1371/journal.pone.0038746] [PMID: 22723882]
[16]
Zheng, J.; Wang, Q.; Leng, W.; Sun, X.; Peng, J. Bone marrow-derived mesenchymal stem cell-conditioned medium attenuates tubulointerstitial fibrosis by inhibiting monocyte mobilization in an irreversible model of unilateral ureteral obstruction. Mol. Med. Rep., 2018, 17(6), 7701-7707.
[http://dx.doi.org/10.3892/mmr.2018.8848] [PMID: 29620281]
[17]
Gunawardena, T.N.A.; Rahman, M.T.; Abdullah, B.J.J.; Abu Kasim, N.H. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J. Tissue Eng. Regen. Med., 2019, 13(4), 569-586.
[http://dx.doi.org/10.1002/term.2806] [PMID: 30644175]
[18]
Semenza, G.L.; Wang, G.L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol., 1992, 12(12), 5447-5454.
[PMID: 1448077]
[19]
Requena-Ibáñez, J.A.; Santos-Gallego, C.G.; Rodriguez-Cordero, A.; Zafar, M.U.; Badimon, J.J. Prolyl hydroxylase inhibitors: A new opportunity in renal and myocardial protection. Cardiovasc. Drugs Ther., 2021, 36(6), 1187-1196.
[PMID: 34533692]
[20]
Singh, A.K.; Kolligundla, L.P.; Francis, J.; Pasupulati, A.K. Detrimental effects of hypoxia on glomerular podocytes. J. Physiol. Biochem., 2021, 77(2), 193-203.
[http://dx.doi.org/10.1007/s13105-021-00788-y] [PMID: 33835424]
[21]
Ruas, J.L.; Poellinger, L.; Pereira, T. Role of CBP in regulating HIF-1-mediated activation of transcription. J. Cell Sci., 2005, 118(2), 301-311.
[http://dx.doi.org/10.1242/jcs.01617] [PMID: 15615775]
[22]
Wei, X.; Zhu, X.; Jiang, L.; Huang, X.; Zhang, Y.; Zhao, D.; Du, Y. Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis. Int. Urol. Nephrol., 2020, 52(7), 1287-1295.
[http://dx.doi.org/10.1007/s11255-020-02474-2] [PMID: 32378138]
[23]
Tanaka, T.; Nangaku, M. The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens., 2010, 19(1), 43-50.
[http://dx.doi.org/10.1097/MNH.0b013e3283328eed] [PMID: 19779337]
[24]
Kimura, K; Iwano, M Molecular mechanisms of tissue fibrosis. Japanese J. Clin. Immunol., 2009, 32, 160-167.
[25]
Ma, T.T.; Meng, X.M. TGF-β/Smad and renal fibrosis. Adv. Exp. Med. Biol., 2019, 1165, 347-364.
[http://dx.doi.org/10.1007/978-981-13-8871-2_16] [PMID: 31399973]
[26]
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(3), 207.
[http://dx.doi.org/10.3390/cells8030207] [PMID: 30823476]
[27]
Dasgupta, S.; Lonard, D.M.; O’Malley, B.W. Nuclear receptor coactivators: Master regulators of human health and disease. Annu. Rev. Med., 2014, 65(1), 279-292.
[http://dx.doi.org/10.1146/annurev-med-051812-145316] [PMID: 24111892]
[28]
Oñate, S.A.; Tsai, S.Y.; Tsai, M.J.; O’Malley, B.W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science, 1995, 270(5240), 1354-1357.
[http://dx.doi.org/10.1126/science.270.5240.1354] [PMID: 7481822]
[29]
Carrero, P.; Okamoto, K.; Coumailleau, P.; O’Brien, S.; Tanaka, H.; Poellinger, L. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol. Cell. Biol., 2000, 20(1), 402-415.
[http://dx.doi.org/10.1128/MCB.20.1.402-415.2000] [PMID: 10594042]
[30]
Dennler, S.; Pendaries, V.; Tacheau, C.; Costas, M.A.; Mauviel, A.; Verrecchia, F. The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: Role of p300/CBP. Oncogene, 2005, 24(11), 1936-1945.
[http://dx.doi.org/10.1038/sj.onc.1208343] [PMID: 15688032]
[31]
Salter, R.C.; Foka, P.; Davies, T.S.; Gallagher, H.; Michael, D.R.; Ashlin, T.G.; Ramji, D.P. The role of mitogen-activated protein kinases and sterol receptor coactivator-1 in TGF-β-regulated expression of genes implicated in macrophage cholesterol uptake. Sci. Rep., 2016, 6(1), 34368.
[http://dx.doi.org/10.1038/srep34368] [PMID: 27687241]
[32]
Sun, YB; Qu, X; Caruana, G; Li, J The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Res. Biol. Diver., 2016, 92, 102-107.
[33]
Loeffler, I.; Wolf, G. Transforming growth factor- and the progression of renal disease. Nephrol. Dial. Transplant., 2014, 29(Suppl. 1), i37-i45.
[http://dx.doi.org/10.1093/ndt/gft267] [PMID: 24030832]
[34]
Hills, C.E.; Squires, P.E. The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev., 2011, 22(3), 131-139.
[http://dx.doi.org/10.1016/j.cytogfr.2011.06.002] [PMID: 21757394]
[35]
Zeisberg, M.; Kalluri, R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J. Mol. Med., 2004, 82(3), 175-181.
[http://dx.doi.org/10.1007/s00109-003-0517-9] [PMID: 14752606]
[36]
Flanders, K.C. Smad3 as a mediator of the fibrotic response. Int. J. Exp. Pathol., 2004, 85(2), 47-64.
[http://dx.doi.org/10.1111/j.0959-9673.2004.00377.x] [PMID: 15154911]
[37]
Ye, D.; Wu, S.; Zhang, B.; Hong, C.; Yang, L. Characteristics and clinical potential of a cellularly modified gelatin sponge. J. Appl. Biomater. Funct. Mater., 2021, 19, 22808000211035061.
[http://dx.doi.org/10.1177/22808000211035061] [PMID: 34519565]
[38]
Yang, M.; Cui, Y.; Song, J.; Cui, C.; Wang, L.; Liang, K.; Wang, C.; Sha, S.; He, Q.; Hu, H.; Guo, X.; Zang, N.; Sun, L.; Chen, L. Mesenchymal stem cell-conditioned medium improved mitochondrial function and alleviated inflammation and apoptosis in non-alcoholic fatty liver disease by regulating SIRT1. Biochem. Biophys. Res. Commun., 2021, 546, 74-82.
[http://dx.doi.org/10.1016/j.bbrc.2021.01.098] [PMID: 33578292]
[39]
Tanaka, S.; Tanaka, T.; Nangaku, M. Hypoxia as a key player in the AKI-to-CKD transition. Am. J. Physiol. Renal Physiol., 2014, 307(11), F1187-F1195.
[http://dx.doi.org/10.1152/ajprenal.00425.2014] [PMID: 25350978]
[40]
Janjić, K.; Lilaj, B.; Moritz, A.; Agis, H. Formation of spheroids by dental pulp cells in the presence of hypoxia and hypoxia mimetic agents. Int. Endod. J., 2018, 51(Suppl. 2), e146-e156.
[http://dx.doi.org/10.1111/iej.12806] [PMID: 28656722]
[41]
Misumi, S.; Kim, T.S.; Jung, C.G.; Masuda, T.; Urakawa, S.; Isobe, Y.; Furuyama, F.; Nishino, H.; Hida, H. Enhanced neurogenesis from neural progenitor cells with G1/S-phase cell cycle arrest is mediated by transforming growth factor β1. Eur. J. Neurosci., 2008, 28(6), 1049-1059.
[http://dx.doi.org/10.1111/j.1460-9568.2008.06420.x] [PMID: 18783370]
[42]
Yao, Q.; Liu, Y.; Tao, J.; Baumgarten, K.M.; Sun, H. Hypoxia-mimicking nanofibrous scaffolds promote endogenous bone regeneration. ACS Appl. Mater. Interfaces, 2016, 8(47), 32450-32459.
[http://dx.doi.org/10.1021/acsami.6b10538] [PMID: 27809470]
[43]
Shu, B; Yang, WW; Yang, HT Expression pattern of E2F6 in physical and chemical hypoxia-induced apoptosis. Acta. physiol. Sinica, 2008, 60, 1-10.
[44]
Liu, C.; Tsai, A.L.; Chen, Y.C.; Fan, S.C.; Huang, C.H.; Wu, C.C.; Chang, C.H. Facilitation of human osteoblast apoptosis by sulindac and indomethacin under hypoxic injury. J. Cell. Biochem., 2012, 113(1), 148-155.
[http://dx.doi.org/10.1002/jcb.23338] [PMID: 21882223]
[45]
Lu, L.; Li, J.; Le, Y.; Jiang, H. Inhibitor of growth 4 (ING4) inhibits hypoxia-induced EMT by decreasing HIF-1α and snail in HK2 cells. Acta Histochem., 2019, 121(6), 695-703.
[http://dx.doi.org/10.1016/j.acthis.2019.06.005] [PMID: 31239073]
[46]
Yoshida, K.; Nakashima, A.; Doi, S.; Ueno, T.; Okubo, T.; Kawano, K.; Kanawa, M.; Kato, Y.; Higashi, Y.; Masaki, T. Serum-free medium enhances the immunosuppressive and antifibrotic abilities of mesenchymal stem cells utilized in experimental renal fibrosis. Stem Cells Transl. Med., 2018, 7(12), 893-905.
[http://dx.doi.org/10.1002/sctm.17-0284] [PMID: 30269426]
[47]
Simovic Markovic, B.; Gazdic, M.; Arsenijevic, A.; Jovicic, N.; Jeremic, J.; Djonov, V.; Arsenijevic, N.; Lukic, M.L.; Volarevic, V. Mesenchymal stem cells attenuate cisplatin-induced nephrotoxicity in inos-dependent manner. Stem Cells Int., 2017, 2017, 1-15.
[http://dx.doi.org/10.1155/2017/1315378] [PMID: 28828008]
[48]
Iseri, K.; Iyoda, M.; Ohtaki, H.; Matsumoto, K.; Wada, Y.; Suzuki, T.; Yamamoto, Y.; Saito, T.; Hihara, K.; Tachibana, S.; Honda, K.; Shibata, T. Therapeutic effects and mechanism of conditioned media from human mesenchymal stem cells on anti-GBM glomerulonephritis in WKY rats. Am. J. Physiol. Renal Physiol., 2016, 310(11), F1182-F1191.
[http://dx.doi.org/10.1152/ajprenal.00165.2016] [PMID: 27053690]
[49]
Geng, X.; Hong, Q.; Chi, K.; Wang, S.; Cai, G.; Wu, D. Mesenchymal stem cells loaded with gelatin microcryogels attenuate renal fibrosis. BioMed Res. Int., 2019, 2019, 1-9.
[http://dx.doi.org/10.1155/2019/6749326] [PMID: 31781634]
[50]
Yang, Y; Yu, X; Zhang, Y; Ding, G; Zhu, C; Huang, S; Jia, Z; Zhang, A Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury. Clin. Sci., 2018, 132, 825-838.
[51]
Rajendran, G.; Schonfeld, M.P.; Tiwari, R.; Huang, S.; Torosyan, R.; Fields, T.; Park, J.; Susztak, K.; Kapitsinou, P.P. Inhibition of endothelial phd2 suppresses post-ischemic kidney inflammation through hypoxia-inducible factor-1. J. Am. Soc. Nephrol., 2020, 31(3), 501-516.
[http://dx.doi.org/10.1681/ASN.2019050523] [PMID: 31996410]
[52]
Higgins, D.F.; Kimura, K.; Bernhardt, W.M.; Shrimanker, N.; Akai, Y.; Hohenstein, B.; Saito, Y.; Johnson, R.S.; Kretzler, M.; Cohen, C.D.; Eckardt, K.U.; Iwano, M.; Haase, V.H. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest., 2007, 117(12), 3810-3820.
[http://dx.doi.org/10.1172/JCI30487] [PMID: 18037992]
[53]
Luo, L.; Luo, G.; Fang, Q.; Sun, Z. Stable expression of hypoxia-inducible factor-1α in human renal proximal tubular epithelial cells promotes epithelial to mesenchymal transition. Transplant. Proc., 2014, 46(1), 130-134.
[http://dx.doi.org/10.1016/j.transproceed.2013.06.024] [PMID: 24507038]
[54]
Qin, Q.; Xu, Y.; He, T.; Qin, C.; Xu, J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res., 2012, 22(1), 90-106.
[http://dx.doi.org/10.1038/cr.2011.144] [PMID: 21876555]
[55]
Zhou, J.; Zhang, J.; Xu, M.; Ke, Z.; Zhang, W.; Mai, J. High SRC-1 and Twist1 expression predicts poor prognosis and promotes migration and invasion by inducing epithelial-mesenchymal transition in human nasopharyngeal carcinoma. PLoS One, 2019, 14(4), e0215299.
[http://dx.doi.org/10.1371/journal.pone.0215299] [PMID: 30973923]
[56]
Zhang, J.; Yang, Y.; Liu, H.; Hu, H. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma. Open Med., 2021, 16(1), 1061-1069.
[http://dx.doi.org/10.1515/med-2021-0248] [PMID: 34307888]
[57]
Zhang, Y.; Duan, C.; Bian, C.; Xiong, Y.; Zhang, J. Steroid receptor coactivator-1: A versatile regulator and promising therapeutic target for breast cancer. J. Steroid Biochem. Mol. Biol., 2013, 138, 17-23.
[http://dx.doi.org/10.1016/j.jsbmb.2013.02.010] [PMID: 23474438]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy