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

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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.

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All data generated or analyzed during this study are included in this published article.

Abbreviations

DM:

Diabetes mellitus

DKD:

Diabetic kidney disease

m6A:

N6 methyladenosine

METTL14:

Methyltransferase methyltransferase-like 14

LncRNAs:

Long noncoding RNAs

TUG1:

Taurine upregulated gene 1

STZ:

Streptozotocin

HG:

High glucose

MAPK:

Mitogen-activated protein kinases

ERK:

Extracellular signal-regulation, kinase

JNK:

C-Jun-N-terminal kinase

ERS:

Endoplasmic reticulum stress

RBP:

RNA binding protein

MTT:

3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide

Bcl-2:

B-cell CLL/lymphoma 2

GRP78:

Glucose-regulated protein78

CHOP:

C/EBP homologous protein

EdU:

Ethynyl-2′-deoxyuridine

RIP:

RNA immunoprecipitation

Me-RIP:

Methylated RNA binding protein immunoprecipitation

HE:

Hematoxylin–eosin

Scr:

Serum creatinine

BUN:

Blood urea nitrogen

qRT-PCR:

Quantitative real-time polymerase chain reaction

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This work was supported by Shandong Provincial Medical and Health Development Project (No. 202103060284) and the Research Fund for Academician Lin He New Medicine (No. JYHL2019FMS11).

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Author notes

  1. Co first authors: Yingying Zheng and Zhengjun Zhang

Authors and Affiliations

  1. Health Management Center, Weifang People’s Hospital, Weifang Medical University, Weifang, 261041, Shandong Province, People’s Republic of China

    Yingying Zheng & Dejie Zheng

  2. Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong Province, People’s Republic of China

    Zhengjun Zhang & Pengfei Yi

  3. Department of Thoracic Surgery, Weifang People’s Hospital, Weifang Medical University, Kuiwen District, No. 151, Guangwen Street, Weifang, 261041, Shandong Province, People’s Republic of China

    Shaoqiang Wang

  4. Department of Scientific Research Management, Weifang People’s Hospital, Weifang Medical University, Weifang, 261041, Shandong Province, People’s Republic of China

    Shaoqiang Wang

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Correspondence to Shaoqiang Wang.

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The animal studies were approved by the Animal Care and Use Committee of the Affiliated Hospital of Jining Medical University (JNMC-2020-DW-FY-041).

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592_2023_2145_MOESM1_ESM.tif

Figure S1. HG induced HK2 cell apoptosis and ERS. HK2 cells were subjected to HG (15, 30 and 45 mM) for 24 h. HK-2 cell viability (A) and proliferation (B) were examined by MTT assay and EdU assay, respectively. C Flow cytometry was performed to examine HK2 cell apoptosis. D, E Bax, cleaved-caspase-3, Bcl-2, GRP78, CHOP and caspase12 protein levels were analyzed by western blot. The measurement data were presented as mean  ±  SD. All data was obtained from at least three replicate experiments. *p < 0.05, **p < 0.01, ***p < 0.001 (TIF 2815 KB)

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Zheng, Y., Zhang, Z., Zheng, D. et al. METTL14 promotes the development of diabetic kidney disease by regulating m6A modification of TUG1. Acta Diabetol 60, 1567–1580 (2023). https://doi.org/10.1007/s00592-023-02145-5

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