Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Acta Diabetologica
Erschienen in: Acta Diabetologica 11/2023

10.07.2023 | Original Article

METTL14 promotes the development of diabetic kidney disease by regulating m6A modification of TUG1

verfasst von: Yingying Zheng, Zhengjun Zhang, Dejie Zheng, Pengfei Yi, Shaoqiang Wang

Erschienen in: Acta Diabetologica | Ausgabe 11/2023

Einloggen, um Zugang zu erhalten

Abstract

Background

Diabetic kidney disease (DKD) is one of the most common diabetic complications. Endoplasmic reticulum stress (ERS) is an important step for renal tubular epithelial cell apoptosis during DKD progression. Herein, the role and regulatory mechanism of METTL14 in ERS during DKD progression were investigated.

Methods

DKD animal and cell models were established by streptozotocin (STZ) and high glucose (HG), respectively. HE and Masson staining were performed to analyze renal lesions in DKD mouse. Cell viability and proliferation were determined by MTT and EdU staining, respectively. HK2 cell apoptosis was analyzed by flow cytometry. TUG1 m6A level was determined by Me-RIP. The interaction between TUG1, LIN28B and MAPK1 was analyzed by RIP and RNA pull-down assays.

Results

HG stimulation promoted apoptosis and increased ERS marker proteins (GRP78, CHOP and caspase12) expression in HK2 cells, while these changes were reversed by METTL14 knockdown. METTL14 inhibited TUG1 stability and expression level in an m6A-dependent manner. As expected, TUG1 knockdown abrogated METTL14 knockdown’s inhibition on HG-induced HK2 cell apoptosis and ERS. In addition, TUG1 inactivated MAPK1/ERK signaling by binding with LIN28B. And TUG1 overexpression’s repression on HG-induced HK2 cell apoptosis and ERS was abrogated by MAPK1 signaling activation. Meanwhile, METTL14 knockdown or TUG1 overexpression protected against STZ-induced renal lesions and renal fibrosis in DKD mouse.

Conclusion

METTL14 promoted renal tubular epithelial cell apoptosis and ERS by activating MAPK/ERK pathway through m6A modification of TUG1, thereby accelerating DKD progression.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Maresch CC, Stute DC, Fleming T, Lin J, Hammes HP, Linn T (2019) Hyperglycemia induces spermatogenic disruption via major pathways of diabetes pathogenesis. Sci Rep 9(1):13074PubMedPubMedCentralCrossRef
2.
VR ALBVR, Tan SH, Candasamy M, Bhattamisra SK (2019) Diabetic nephropathy: an update on pathogenesis and drug development. Diabetes Metab Syndr 13(1):754–762 CrossRef
3.
Sharma D, Bhattacharya P, Kalia K, Tiwari V (2017) Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets. Diabetes Res Clin Pract 128:91–108PubMedCrossRef
4.
5.
La Rocca E, Fiorina P, Astorri E, Rossetti C, Lucignani G, Fazio F et al (2000) Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplantation alone in uremic IDDM patients. Cell Transpl 9(6):929–932CrossRef
6.
Petrazzuolo A, Sabiu G, Assi E, Maestroni A, Pastore I, Lunati ME et al (2023) Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease. Pharmacol Res 190:106710PubMedCrossRef
7.
Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochem Biophys Acta 1833(12):3460–3470PubMedCrossRef
8.
Hu H, Tian M, Ding C, Yu S (2018) The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9:3083PubMedCrossRef
9.
He Z, Zhou Y, Huang Y, Wang Q, Zheng B, Zhang H et al (2017) Dl-3-n-butylphthalide improves functional recovery in rats with spinal cord injury by inhibiting endoplasmic reticulum stress-induced apoptosis. Am J Transl Res 9(3):1075–1087PubMedPubMedCentral
10.
Zhang J, Morris MW Jr, Dorsett-Martin WA, Drake LC, Anderson CD (2013) Autophagy is involved in endoplasmic reticulum stress-induced cell death of rat hepatocytes. J Surg Res 183(2):929–935PubMedPubMedCentralCrossRef
11.
Liu G, Sun Y, Li Z, Song T, Wang H, Zhang Y et al (2008) Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease. Biochem Biophys Res Commun 370(4):651–656PubMedCrossRef
12.
13.
Lei L, Bai YH, Jiang HY, He T, Li M, Wang JP (2021) A bioinformatics analysis of the contribution of m6A methylation to the occurrence of diabetes mellitus. Endocr Connect 10(10):1253–1265PubMedPubMedCentralCrossRef
14.
Ma L, Chen T, Zhang X, Miao Y, Tian X, Yu K et al (2021) The m(6)A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol 38:101801PubMedCrossRef
15.
Lu Z, Liu H, Song N, Liang Y, Zhu J, Chen J et al (2021) METTL14 aggravates podocyte injury and glomerulopathy progression through N(6)-methyladenosine-dependent downregulating of Sirt1. Cell Death Dis 12(10):881PubMedPubMedCentralCrossRef
16.
Li M, Deng L, Xu G (2021) METTL14 promotes glomerular endothelial cell injury and diabetic nephropathy via m6A modification of α-klotho. Mol Med 27(1):106PubMedPubMedCentralCrossRef
17.
Schmitz SU, Grote P, Herrmann BG (2016) Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci 73(13):2491–2509PubMedPubMedCentralCrossRef
18.
Zhang H, Yan Y, Hu Q, Zhang X (2021) LncRNA MALAT1/microRNA let-7f/KLF5 axis regulates podocyte injury in diabetic nephropathy. Life Sci 266:118794PubMedCrossRef
19.
Ge Y, Wang J, Wu D, Zhou Y, Qiu S, Chen J et al (2019) lncRNA NR_038323 suppresses renal fibrosis in diabetic nephropathy by targeting the miR-324-3p/DUSP1 Axis. Mol Ther Nucleic Acids 17:741–753PubMedPubMedCentralCrossRef
20.
Wang WY, Wang YF, Ma P, Xu TP, Shu YQ (2017) Taurine-upregulated gene 1: a vital long non-coding RNA associated with cancer in humans. Mol Med Rep 16(5):6467–6471PubMedCrossRef
21.
Li SY, Susztak K (2016) The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes. J Clin Invest 126(11):4072–4075PubMedPubMedCentralCrossRef
22.
Wang F, Gao X, Zhang R, Zhao P, Sun Y, Li C (2019) LncRNA TUG1 ameliorates diabetic nephropathy by inhibiting miR-21 to promote TIMP3-expression. Int J Clin Exp Pathol 12(3):717–729PubMedPubMedCentral
23.
Lei X, Zhang L, Li Z, Ren J (2018) Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats. Drug Des Dev Ther 12:2785–2793CrossRef
24.
Meng L, Lin H, Huang X, Weng J, Peng F, Wu S (2022) METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA. Cell Death Dis 13(1):38PubMedPubMedCentralCrossRef
25.
Xin X, Khan ZA, Chen S, Chakrabarti S (2004) Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis. Lab Investig 84(11):1451–1459PubMedCrossRef
26.
Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF (2015) Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res 35(6):600–604PubMedCrossRef
27.
Liu Y, Chen J, Liang H, Cai Y, Li X, Yan L et al (2022) Human umbilical cord-derived mesenchymal stem cells not only ameliorate blood glucose but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling. Stem Cell Res Ther 13(1):258PubMedPubMedCentralCrossRef
28.
Cheng S, Li L, Song C, Jin H, Ma S, Kang P (2020) Sitagliptin relieves diabetic nephropathy fibrosis via the MAPK/ERK signaling pathway. Minerva Endocrinol 45(3):273–275PubMedCrossRef
29.
Jin J, Ma Y, Tong X, Yang W, Dai Y, Pan Y et al (2020) Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK. Hum Reprod 35(5):1145–1158PubMedPubMedCentralCrossRef
30.
Victor P, Umapathy D, George L, Juttada U, Ganesh GV, Amin KN et al (2021) Crosstalk between endoplasmic reticulum stress and oxidative stress in the progression of diabetic nephropathy. Cell Stress Chaperones 26(2):311–321PubMedCrossRef
31.
Xu J, Liu L, Gan L, Hu Y, Xiang P, Xing Y et al (2021) Berberine acts on C/EBPβ/lncRNA Gas5/miR-18a-5p loop to decrease the mitochondrial ROS generation in HK-2 Cells. Front Endocrinol 12:675834CrossRef
32.
Cheng Q, Pan J, Zhou ZL, Yin F, Xie HY, Chen PP et al (2021) Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy. Acta Pharmacol Sin 42(6):954–963PubMedCrossRef
33.
Yu XZ, Yang BW, Ao MY, Wu YK, Ye H, Wang RY et al (2023) CircNFIX stimulates the proliferation, invasion, and stemness properties of ovarian cancer cells by enhancing SH3RF3 mRNA stability via binding LIN28B. Kaohsiung J Med Sci 39(3):234–243PubMedCrossRef
34.
35.
36.
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149(7):1635–1646PubMedPubMedCentralCrossRef
37.
Engin F, Hotamisligil GS (2010) Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab 12(Suppl 2):108–115PubMedCrossRef
38.
Ju Y, Su Y, Chen Q, Ma K, Ji T, Wang Z et al (2019) Protective effects of astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. Biomed Pharmacother 109:84–92PubMedCrossRef
39.
Huang S, Xu Y, Ge X, Xu B, Peng W, Jiang X et al (2019) Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway. J Cell Physiol 234(7):11200–11207PubMedCrossRef
40.
Zhang J, Jiang T, Liang X, Shu S, Xiang X, Zhang W et al (2019) lncRNA MALAT1 mediated high glucose-induced HK-2 cell epithelial-to-mesenchymal transition and injury. J Physiol Biochem 75(4):443–452PubMedCrossRef
41.
Pereira B, Billaud M, Almeida R (2017) RNA-binding proteins in cancer: old players and new actors. Trends Cancer 3(7):506–528PubMedCrossRef
42.
Liu Z, Bian M, Pang L (2023) LncRNA CRNDE binds hnRNPA1 to facilitate carbon monoxide poisoning-induced delayed encephalopathy via inhibiting UCHL5-mediated SMO deubiquitination. Metab Brain Dis 38(3):1097–1113PubMedCrossRef
43.
Tao W, Ma J, Zheng J, Liu X, Liu Y, Ruan X et al (2020) Silencing SCAMP1-TV2 inhibited the malignant biological behaviors of breast cancer cells by interaction with PUM2 to facilitate INSM1 mRNA degradation. Front Oncol 10:613PubMedPubMedCentralCrossRef
44.
Zou H, Luo J, Guo Y, Liu Y, Wang Y, Deng L et al (2022) RNA-binding protein complex LIN28/MSI2 enhances cancer stem cell-like properties by modulating Hippo-YAP1 signaling and independently of Let-7. Oncogene 41(11):1657–1672PubMedPubMedCentralCrossRef
45.
Qin H, Li W, Sun Y, Bao Y, Sun L, Song Z et al (2018) 20(S)-25-methoxyl-dammarane-3β,12β,20-triol attenuates endoplasmic reticulum stress via ERK/MAPK signaling pathway. Eur J Pharmacol 836:75–82PubMedCrossRef
46.
Toyoda M, Suzuki D, Honma M, Uehara G, Sakai T, Umezono T et al (2004) High expression of PKC-MAPK pathway mRNAs correlates with glomerular lesions in human diabetic nephropathy. Kidney Int 66(3):1107–1114PubMedCrossRef
47.
Zhang J, Jing S, Zhang H, Zhang J, Xie H, Feng L (2022) Low-dose aspirin prevents LPS-induced preeclampsia-like phenotype via AQP-1 and the MAPK/ERK 1/2 pathway. Placenta 121:61–69PubMedCrossRef
48.
Metadaten
Titel
METTL14 promotes the development of diabetic kidney disease by regulating m6A modification of TUG1
verfasst von
Yingying Zheng
Zhengjun Zhang
Dejie Zheng
Pengfei Yi
Shaoqiang Wang
Publikationsdatum
10.07.2023
Verlag
Springer Milan
Erschienen in
Acta Diabetologica / Ausgabe 11/2023
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-023-02145-5

Weitere Artikel der Ausgabe 11/2023

Acta Diabetologica 11/2023 Zur Ausgabe

Position Statement

Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects

Letter to the Editor

Letter to editor: Effect of obesity on fragility fractures, BMD and vitamin D levels in postmenopausal women. Influence of type 2 diabetes mellitus

Original Article

A cohort follow-up study for diabetic retinopathy screening incidence in the North Denmark Region

Original Article

Pregestational exposure to hormonal combined contraceptives and risk of gestational diabetes: an observational retrospective population study

Original Article

Coexisiting type 1 diabetes and celiac disease is associated with lower Hba1c when compared to type 1 diabetes alone: data from the Australasian Diabetes Data Network (ADDN) registry

Original Article

Bariatric surgery in individuals with type 2 diabetes is not associated with short or long-term risk of diabetic retinopathy progression: results from a nationwide cohort study

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Erhöhte Mortalität bei postpartalem Brustkrebs

07.05.2024 Mammakarzinom Nachrichten

Auch für Trägerinnen von BRCA-Varianten gilt: Erkranken sie fünf bis zehn Jahre nach der letzten Schwangerschaft an Brustkrebs, ist das Sterberisiko besonders hoch.

Hypertherme Chemotherapie bietet Chance auf Blasenerhalt

07.05.2024 Harnblasenkarzinom Nachrichten

Eine hypertherme intravesikale Chemotherapie mit Mitomycin kann für Patienten mit hochriskantem nicht muskelinvasivem Blasenkrebs eine Alternative zur radikalen Zystektomie darstellen. Kölner Urologen berichten über ihre Erfahrungen.

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

07.05.2024 Medizinstudium Nachrichten

Extreme Arbeitsverdichtung und kaum Supervision: Dr. Andrea Martini, Sprecherin des Bündnisses Junge Ärztinnen und Ärzte (BJÄ) über den Frust des ärztlichen Nachwuchses und die Vorteile des Rucksack-Modells.

Vorhofflimmern bei Jüngeren gefährlicher als gedacht

06.05.2024 Vorhofflimmern Nachrichten

Immer mehr jüngere Menschen leiden unter Vorhofflimmern. Betroffene unter 65 Jahren haben viele Risikofaktoren und ein signifikant erhöhtes Sterberisiko verglichen mit Gleichaltrigen ohne die Erkrankung.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise