Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

MiR-29b Alleviates High Glucose-induced Inflammation and Apoptosis in Podocytes by Down-regulating PRKAB2

Author(s): Hongxiu Du, Yakun Wang, Yingchun Zhu, Xiaoying Li, Tingying Zhu, Qianqian Wu and Fangfang Zha*

Volume 24, Issue 8, 2024

Published on: 08 January, 2024

Page: [981 - 990] Pages: 10

DOI: 10.2174/0118715303267375231204103200

open access plus

Open Access Journals Promotions 2
conference banner
Abstract

Background: Podocyte injury and inflammatory response are the core contributors to the pathogenesis of diabetic nephropathy. This study aims to identify novel regulatory miRNAs and elucidate their underlying mechanisms, which will help us understand the pathogenesis of diabetic nephropathy more comprehensively.

Materials and Methods: Different glucose concentrations were used to treat podocytes to mimic the pathology of diabetic nephropathy in vitro. Flow cytometry was used to determine cell apoptosis. Inflammatory cytokines released by podocytes were measured by using an enzymelinked immunosorbent assay (ELISA). Western Blot was used to detect the expression of PRKAB2 protein in podocytes.

Results: Genecard and g: profiler results revealed that miR-29b might be involved in regulating HG-induced cell injury. QRT-PCR indicated that HG-induced downregulation of miR-29b in podocytes. MiR-29b knockdown promoted cell apoptosis and inflammatory response in podocytes. MiR-29b overexpression repressed cell apoptosis and inflammatory response induced by high glucose treatment in podocytes. Luciferase reporter assay and Western Blot showed that miR-29b targeted PRKAB2 to negatively regulate PRKAB2 expression directly. Knockdown of PRKAB2 reversed the increased cell apoptosis and inflammation induced by miR-29b inhibitors.

Conclusion: MiR-29b plays a role in inhibiting inflammation and apoptosis in high glucose (HG) treated podocytes by negatively regulating PRKAB2 expression. This study provides new potential targets and ideas for the treatment of diabetic nephropathy.

Keywords: Cell apoptosis, diabetic nephropathy, inflammation, microRNAs, podocytes, PRKAB2 protein.

« Previous
Graphical Abstract
[1]
Kanda, H.; Hirasaki, Y.; Iida, T.; Kanao-Kanda, M.; Toyama, Y.; Chiba, T.; Kunisawa, T. Perioperative management of patients with end-stage renal disease. J. Cardiothorac. Vasc. Anesth., 2017, 31(6), 2251-2267.
[http://dx.doi.org/10.1053/j.jvca.2017.04.019] [PMID: 28803771]
[2]
Krolewski, A.S.; Skupien, J.; Rossing, P.; Warram, J.H. Fast renal decline to end-stage renal disease: An unrecognized feature of nephropathy in diabetes. Kidney Int., 2017, 91(6), 1300-1311.
[http://dx.doi.org/10.1016/j.kint.2016.10.046] [PMID: 28366227]
[3]
Qi, C.; Mao, X.; Zhang, Z.; Wu, H. Classification and differential diagnosis of diabetic nephropathy. J. Diabetes Res., 2017, 2017, 1-7.
[http://dx.doi.org/10.1155/2017/8637138] [PMID: 28316995]
[4]
Campbell, KN; Tumlin, JA Protecting podocytes: A key target for therapy of focal segmental glomerulosclerosis. Am J Nephrol, 2018, 47(Suppl 1), 14-29.
[http://dx.doi.org/10.1159/000481634]
[5]
Podgórski, P.; Konieczny, A.; Lis, Ł.; Witkiewicz, W.; Hruby, Z. Glomerular podocytes in diabetic renal disease. Adv. Clin. Exp. Med., 2019, 28(12), 1711-1715.
[http://dx.doi.org/10.17219/acem/104534] [PMID: 31851794]
[6]
Qin, X.; Jiang, M.; Zhao, Y.; Gong, J.; Su, H.; Yuan, F.; Fang, K.; Yuan, X.; Yu, X.; Dong, H.; Lu, F. Berberine protects against diabetic kidney disease via promoting PGC‐1α‐regulated mitochondrial energy homeostasis. Br. J. Pharmacol., 2020, 177(16), 3646-3661.
[http://dx.doi.org/10.1111/bph.14935] [PMID: 31734944]
[7]
Ren, F.; Zhang, M.; Zhang, C.; Sang, H. Psoriasis-like inflammation induced renal dysfunction through the tlr/nf-κB signal pathway. BioMed Res. Int., 2020, 2020, 1-11.
[http://dx.doi.org/10.1155/2020/3535264] [PMID: 32090080]
[8]
Takao, T.; Yanagisawa, H.; Suka, M.; Yoshida, Y.; Onishi, Y.; Tahara, T.; Kikuchi, T.; Kushiyama, A.; Anai, M.; Takahashi, K.; Wakabayashi Sugawa, S.; Yamazaki, H.; Kawazu, S.; Iwamoto, Y.; Noda, M.; Kasuga, M. Synergistic association of the copper/zinc ratio under inflammatory conditions with diabetic kidney disease in patients with type 2 diabetes: The asahi diabetes complications study. J. Diabetes Investig., 2022, 13(2), 299-307.
[http://dx.doi.org/10.1111/jdi.13659] [PMID: 34533892]
[9]
Matoba, K.; Takeda, Y.; Nagai, Y.; Kawanami, D.; Utsunomiya, K.; Nishimura, R. Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease. Int. J. Mol. Sci., 2019, 20(14), 3393.
[http://dx.doi.org/10.3390/ijms20143393] [PMID: 31295940]
[10]
Su, J.; Ye, D.; Gao, C.; Huang, Q.; Gui, D. Mechanism of progression of diabetic kidney disease mediated by podocyte mitochondrial injury. Mol. Biol. Rep., 2020, 47(10), 8023-8035.
[http://dx.doi.org/10.1007/s11033-020-05749-0] [PMID: 32918716]
[11]
He, J.; Wu, J.; Dong, S.; Xu, J.; Wang, J.; Zhou, X.; Rao, Z.; Gao, W. Exosome-encapsulated miR-31, miR-192, and miR-375 serve as clinical biomarkers of gastric cancer. J. Oncol., 2023, 2023, 1-10.
[http://dx.doi.org/10.1155/2023/7335456] [PMID: 36844871]
[12]
Sun, F.; Yu, P.F.; Wang, D.; Teng, J. MicroRNA-488 regulates diabetic nephropathy via TGF-β1 pathway. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(10), 4333-4340.
[PMID: 31173306]
[13]
Iranzad, R.; Motavalli, R.; Ghassabi, A.; Pourakbari, R.; Etemadi, J.; Yousefi, M. Roles of microRNAs in renal disorders related to primary podocyte dysfunction. Life Sci., 2021, 277, 119463.
[http://dx.doi.org/10.1016/j.lfs.2021.119463] [PMID: 33862110]
[14]
Zhou, H.; Ni, W.J.; Meng, X.M.; Tang, L.Q. MicroRNAs as regulators of immune and inflammatory responses: Potential therapeutic targets in diabetic nephropathy. Front. Cell Dev. Biol., 2021, 8, 618536.
[http://dx.doi.org/10.3389/fcell.2020.618536] [PMID: 33569382]
[15]
Guo, J.; Li, J.; Zhao, J.; Yang, S.; Wang, L.; Cheng, G.; Liu, D.; Xiao, J.; Liu, Z.; Zhao, Z. MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin. Sci. Rep., 2017, 7(1), 2314.
[http://dx.doi.org/10.1038/s41598-017-01027-5] [PMID: 28539664]
[16]
Zhao, S.M.; Zhang, T.; Qiu, Q.; Xu, C.; Ma, L.J.; Liu, J.; Wang, Z.; Li, Y.C.; Huang, J.; Zhang, M. MiRNA-337 leads to podocyte injury in mice with diabetic nephropathy. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(19), 8485-8492.
[PMID: 31646579]
[17]
Gondaliya, P.; P Dasare, A.; Jash, K.; Tekade, R.K.; Srivastava, A.; Kalia, K. miR-29b attenuates histone deacetylase-4 mediated podocyte dysfunction and renal fibrosis in diabetic nephropathy. J. Diabetes Metab. Disord., 2019, 19(1), 13-27.
[http://dx.doi.org/10.1007/s40200-019-00469-0] [PMID: 32550152]
[18]
Zhang, C.; Zhong, T.; Li, Y.; Li, X.; Yuan, X.; Liu, L.; Wu, W.; Wu, J.; Wu, Y.; Liang, R.; Xie, X.; Kang, C.; Liu, Y.; Lai, Z.; Xiao, J.; Tang, Z.; Jin, R.; Wang, Y.; Xiao, Y.; Zhang, J.; Li, J.; Liu, Q.; Sun, Z.; Zhong, J. The hepatic AMPK-TET1-SIRT1 axis regulates glucose homeostasis. eLife, 2021, 10, e70672.
[http://dx.doi.org/10.7554/eLife.70672] [PMID: 34738906]
[19]
Prochazka, M.; Farook, V.S.; Ossowski, V.; Wolford, J.K.; Bogardus, C. Variant screening of PRKAB2, a type 2 diabetes mellitus susceptibility candidate gene on 1q in Pima Indians. Mol. Cell. Probes, 2002, 16(6), 421-427.
[http://dx.doi.org/10.1006/mcpr.2002.0439] [PMID: 12490143]
[20]
Guo, F.; Wang, W.; Song, Y.; Wu, L.; Wang, J.; Zhao, Y.; Ma, X.; Ji, H.; Liu, Y.; Li, Z.; Qin, G. LncRNA SNHG17 knockdown promotes Parkin-dependent mitophagy and reduces apoptosis of podocytes through Mst1. Cell Cycle, 2020, 19(16), 1997-2006.
[http://dx.doi.org/10.1080/15384101.2020.1783481] [PMID: 32627655]
[21]
Li, F.; Dai, B.; Ni, X. Long non-coding RNA cancer susceptibility candidate 2 (CASC2) alleviates the high glucose-induced injury of CIHP-1 cells via regulating miR-9-5p/PPARγ axis in diabetes nephropathy. Diabetol. Metab. Syndr., 2020, 12(1), 68.
[http://dx.doi.org/10.1186/s13098-020-00574-8] [PMID: 32774472]
[22]
Chen, J.; Xu, Q.; Zhang, W.; Zhen, Y.; Cheng, F.; Hua, G.; Lan, J.; Tu, C. MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression. Open Life Sci., 2020, 15(1), 939-950.
[http://dx.doi.org/10.1515/biol-2020-0088] [PMID: 33817280]
[23]
Kim, S.K.; Kim, G.; Choi, B.H.; Ryu, D.; Ku, S.K.; Kwak, M.K. Negative correlation of urinary miR-199a-3p level with ameliorating effects of sarpogrelate and cilostazol in hypertensive diabetic nephropathy. Biochem. Pharmacol., 2021, 184, 114391.
[http://dx.doi.org/10.1016/j.bcp.2020.114391] [PMID: 33359069]
[24]
Bhattacharjee, N.; Barma, S.; Konwar, N.; Dewanjee, S.; Manna, P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur. J. Pharmacol., 2016, 791, 8-24.
[http://dx.doi.org/10.1016/j.ejphar.2016.08.022] [PMID: 27568833]
[25]
Ioannou, K. Diabetic nephropathy: Is it always there? Assumptions, weaknesses and pitfalls in the diagnosis. Hormones, 2017, 16(4), 351-361.
[PMID: 29518755]
[26]
Tagawa, A.; Yasuda, M.; Kume, S.; Yamahara, K.; Nakazawa, J.; Chin-Kanasaki, M.; Araki, H.; Araki, S.; Koya, D.; Asanuma, K.; Kim, E.H.; Haneda, M.; Kajiwara, N.; Hayashi, K.; Ohashi, H.; Ugi, S.; Maegawa, H.; Uzu, T. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes, 2016, 65(3), 755-767.
[http://dx.doi.org/10.2337/db15-0473] [PMID: 26384385]
[27]
He, J.; Hong, Q.; Chen, B.; Cui, S.; Liu, R.; Cai, G.; Guo, J.; Chen, X. Ginsenoside Rb1 alleviates diabetic kidney podocyte injury by inhibiting aldose reductase activity. Acta Pharmacol. Sin., 2022, 43(2), 342-353.
[http://dx.doi.org/10.1038/s41401-021-00788-0] [PMID: 34811512]
[28]
Bose, M.; Almas, S.; Prabhakar, S. Wnt signaling and podocyte dysfunction in diabetic nephropathy. J. Investig. Med., 2017, 65(8), 1093-1101.
[http://dx.doi.org/10.1136/jim-2017-000456] [PMID: 28935636]
[29]
Cao, A.; Li, J.; Asadi, M.; Basgen, J.M.; Zhu, B.; Yi, Z.; Jiang, S.; Doke, T.; El Shamy, O.; Patel, N.; Cravedi, P.; Azeloglu, E.U.; Campbell, K.N.; Menon, M.; Coca, S.; Zhang, W.; Wang, H.; Zen, K.; Liu, Z.; Murphy, B.; He, J.C.; D’Agati, V.D.; Susztak, K.; Kaufman, L. DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity. J. Clin. Invest., 2021, 131(10), e141279.
[http://dx.doi.org/10.1172/JCI141279] [PMID: 33998601]
[30]
Mohr, A.; Mott, J. Overview of microRNA biology. Semin. Liver Dis., 2015, 35(1), 003-011.
[http://dx.doi.org/10.1055/s-0034-1397344] [PMID: 25632930]
[31]
Jiang, Z.H.; Tang, Y.Z.; Song, H.N.; Yang, M.; Li, B.; Ni, C.L. miRNA-342 suppresses renal interstitial fibrosis in diabetic nephropathy by targeting SOX6. Int. J. Mol. Med., 2020, 45(1), 45-52.
[PMID: 31746345]
[32]
He, M.; Wang, J.; Yin, Z.; Zhao, Y.; Hou, H.; Fan, J.; Li, H.; Wen, Z.; Tang, J.; Wang, Y.; Wang, D.W.; Chen, C. MiR-320a induces diabetic nephropathy via inhibiting MafB. Aging (Albany NY), 2019, 11(10), 3055-3079.
[http://dx.doi.org/10.18632/aging.101962] [PMID: 31102503]
[33]
Zhao, Y.; Li, D.; Zhou, P.; Zhao, Y.; Kuang, J. microRNA-29b-3p attenuates diabetic nephropathy in mice by modifying EZH2. Hormones (Athens), 2023, 22(2), 223-233.
[http://dx.doi.org/10.1007/s42000-022-00426-2] [PMID: 36692688]
[34]
Akpınar, K.; Aslan, D.; Fenkçi, S.M.; Caner, V. miR-21-3p and miR-192-5p in patients with type 2 diabetic nephropathy. Diagnosis (Berl.), 2022, 9(4), 499-507.
[http://dx.doi.org/10.1515/dx-2022-0036] [PMID: 35976169]
[35]
Ismail, A.; El-Mahdy, H.A.; Eldeib, M.G.; Doghish, A.S. miRNAs as cornerstones in diabetic microvascular complications. Mol. Genet. Metab., 2023, 138(1), 106978.
[http://dx.doi.org/10.1016/j.ymgme.2022.106978] [PMID: 36565688]
[36]
Schellinger, I.N.; Wagenhäuser, M.; Chodisetti, G.; Mattern, K.; Dannert, A.; Petzold, A.; Jakubizka-Smorag, J.; Emrich, F.; Haunschild, J.; Schuster, A.; Schwob, E.; Schulz, K.; Maegdefessel, L.; Spin, J.M.; Stumvoll, M.; Hasenfuß, G.; Tsao, P.S.; Raaz, U. MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening. Mol. Ther. Nucleic Acids, 2021, 24, 188-199.
[http://dx.doi.org/10.1016/j.omtn.2021.02.021] [PMID: 33767915]
[37]
Zeng, K.; Wang, Y.; Yang, N.; Wang, D.; Li, S.; Ming, J.; Wang, J.; Yu, X.; Song, Y.; Zhou, X.; Deng, B.; Wu, X.; Huang, L.; Yang, Y. Resveratrol inhibits diabetic-induced müller cells apoptosis through MicroRNA-29b/Specificity protein 1 pathway. Mol. Neurobiol., 2017, 54(6), 4000-4014.
[http://dx.doi.org/10.1007/s12035-016-9972-5] [PMID: 27311771]
[38]
Ha, Z.L.; Yu, Z.Y. Downregulation of MIR ‐29b‐3p aggravates podocyte injury by targeting HDAC4 in LPS ‐induced acute kidney injury. Kaohsiung J. Med. Sci., 2021, 37(12), 1069-1076.
[http://dx.doi.org/10.1002/kjm2.12431] [PMID: 34369661]
[39]
Wang, Y.; Liu, T.; Xiao, W.; Bai, Y.; Yue, D.; Feng, L. Ox-LDL induced profound changes of small non-coding RNA in rat endothelial cells. Front. Cardiovasc. Med., 2023, 10, 1060719.
[http://dx.doi.org/10.3389/fcvm.2023.1060719] [PMID: 36824457]
[40]
Ma, X.; Yun, H.J.; Elkin, K.; Guo, Y.; Ding, Y.; Li, G. MicroRNA-29b suppresses inflammation and protects blood-brain barrier integrity in ischemic stroke. Mediators Inflamm., 2022, 2022, 1-11.
[http://dx.doi.org/10.1155/2022/1755416] [PMID: 36052307]
[41]
Li, G.; Ma, X.; Zhao, H.; Fan, J.; Liu, T.; Luo, Y.; Guo, Y. Long non‐coding RNA H19 promotes leukocyte inflammation in ischemic stroke by targeting the miR‐29b/C1QTNF6 axis. CNS Neurosci. Ther., 2022, 28(6), 953-963.
[http://dx.doi.org/10.1111/cns.13829] [PMID: 35322553]
[42]
Zhou, K.; Yin, F.; Li, Y.; Ma, C.; Liu, P.; Xin, Z.; Ren, R.; Wei, S.; Khan, M.; Wang, H.; Zhang, H. MicroRNA-29b ameliorates hepatic inflammation via suppression of STAT3 in alcohol-associated liver disease. Alcohol, 2022, 99, 9-22.
[http://dx.doi.org/10.1016/j.alcohol.2021.10.003] [PMID: 34688828]

© 2024 Bentham Science Publishers | Privacy Policy