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ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes

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Diabetologia Aims and scope Submit manuscript

Abstract

Aims

Lactate accumulation is reported to be a biomarker for diabetic nephropathy progression. Lactate drives lysine lactylation, a newly discovered post-translational modification that is involved in the pathogenesis of cancers and metabolic and inflammatory disease. Here, we aimed to determine whether lysine lactylation is involved in the pathogenesis of diabetic nephropathy.

Methods

Renal biopsy samples from individuals with diabetic nephropathy (n=22) and control samples from individuals without diabetes and kidney disease (n=9) were obtained from the First Affiliated Hospital of Zhengzhou University for immunohistochemical staining. In addition, we carried out global lactylome profiling of kidney tissues from db/m and db/db mice using LC-MS/MS. Furthermore, we assessed the role of lysine lactylation and acyl-CoA synthetase family member 2 (ACSF2) in mitochondrial function in human proximal tubular epithelial cells (HK-2).

Results

The expression level of lysine lactylation was significantly increased in the kidneys of individuals with diabetes as well as in kidneys from db/db mice. Integrative lactylome analysis of the kidneys of db/db and db/m mice identified 165 upregulated proteins and 17 downregulated proteins, with an increase in 356 lysine lactylation sites and a decrease in 22 lysine lactylation sites decreased. Subcellular localisation analysis revealed that most lactylated proteins were found in the mitochondria (115 proteins, 269 sites). We further found that lactylation of the K182 site in ACSF2 contributes to mitochondrial dysfunction. Finally, the expression of ACSF2 was notably increased in the kidneys of db/db mice and individuals with diabetic nephropathy.

Conclusions

Our study strongly suggests that lysine lactylation and ACSF2 are mediators of mitochondrial dysfunction and may contribute to the progression of diabetic nephropathy.

Data availability

The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD050070.

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Abbreviations

ACSF2:

Acyl-CoA synthetase family member 2

DRP1:

Dynamin-related protein 1

ESRD:

End-stage renal disease

FerrDb:

Ferroptosis database

HBSS:

Hanks’ balanced salt solution

IHC:

Immunohistochemical

K182la:

Lysine lactylation at site 182

KEGG:

Kyoto Encyclopedia of Genes and Genomes

Kla:

Lysine lactylation

LCFA:

Long-chain fatty acids

MFN2:

Mitofusin 2

Pan-Kla:

Pan-antibody of lactylation

PAS:

Periodic acid–Schiff

PI3K:

Phosphoinositide 3-kinase

PMSF:

Phenylmethylsulfonyl fluoride

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid

TFAM:

Mitochondrial transcription factor A

UACR:

Urine albumin/creatinine ratio

WT:

Wild-type

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Author information

Author notes

  1. Jingfang Chen and Qi Feng contributed equally to this study.

Authors and Affiliations

  1. Traditional Chinese Medicine Integrated Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Jingfang Chen, Qi Feng, Shaokang Pan, Lulu Liang, Yong Liu, Xiaonan Zhang, Dongwei Liu & Zhangsuo Liu

  2. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China

    Jingfang Chen, Qi Feng, Yingjin Qiao, Shaokang Pan, Lulu Liang, Yong Liu, Xiaonan Zhang, Dongwei Liu & Zhangsuo Liu

  3. Henan Province Research Center for Kidney Disease, Zhengzhou, China

    Jingfang Chen, Qi Feng, Yingjin Qiao, Shaokang Pan, Lulu Liang, Yong Liu, Xiaonan Zhang, Dongwei Liu & Zhangsuo Liu

  4. Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China

    Jingfang Chen, Qi Feng, Yingjin Qiao, Shaokang Pan, Lulu Liang, Yong Liu, Xiaonan Zhang, Dongwei Liu & Zhangsuo Liu

  5. National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China

    Zhihong Liu

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  1. Jingfang Chen
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Corresponding authors

Correspondence to Dongwei Liu, Zhihong Liu or Zhangsuo Liu.

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Acknowledgements

We thank the Biobank of the First Affiliated Hospital of Zhengzhou University (China Human Genetic Resources Preservation Approval No. [2022]BC0079) for providing human control kidney tissues.

Data availability

The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD050070.

Funding

This study is supported by grants from the National Natural Science Foundation of China General Project (no. 81970633), National Natural Science Foundation of China Young Scientists Project (no. 82200796), Medical Science and Technology Research Project of Henan Province (SBGJ202102145) and Natural Science Foundation of Henan Province Excellent Young Scientists Fund Program (no. 202300410363).

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

DL, ZsL and ZhL designed the study; JC, QF, YQ and SP conducted the experiments. LL, YL and XZ were responsible for feeding the mice, measuring weight and blood glucose levels and collecting kidney tissues and serum samples. LL, YL and XZ collected samples of human kidney tissues. YQ, LL,YL and XZ conducted the statistical analysis. JC and QF wrote the manuscript and SP, LL and YL drew the figures. YQ, SP, LL, YL and XZ contributed to drafting the manuscript. JC, QF, LL, DL, ZhL and ZsL revised the manuscript. All authors approved the final version of the manuscript. ZsL is the guarantor of this work.

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Chen, J., Feng, Q., Qiao, Y. et al. ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes. Diabetologia (2024). https://doi.org/10.1007/s00125-024-06156-x

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