ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes

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

doi:10.1007/s00125-024-06156-x

ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes

Diabetologia. 2024 Apr 27. doi: 10.1007/s00125-024-06156-x. Online ahead of print.

Authors

Jingfang Chen^#^{1

2

3

4}, Qi Feng^#^{1

2

3

4}, Yingjin Qiao^{2

3

4}, Shaokang Pan^{1

2

3

4}, Lulu Liang^{1

2

3

4}, Yong Liu^{1

2

3

4}, Xiaonan Zhang^{1

2

3

4}, Dongwei Liu^{5

6

7

8}, Zhihong Liu⁹, Zhangsuo Liu^{10

11

12

13}

Affiliations

¹ Traditional Chinese Medicine Integrated Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
³ Henan Province Research Center for Kidney Disease, Zhengzhou, China.
⁴ Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
⁵ Traditional Chinese Medicine Integrated Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. liu-dongwei@zzu.edu.cn.
⁶ Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China. liu-dongwei@zzu.edu.cn.
⁷ Henan Province Research Center for Kidney Disease, Zhengzhou, China. liu-dongwei@zzu.edu.cn.
⁸ Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China. liu-dongwei@zzu.edu.cn.
⁹ National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. liuzhihong@nju.edu.cn.
¹⁰ Traditional Chinese Medicine Integrated Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. zhangsuoliu@zzu.edu.cn.
¹¹ Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China. zhangsuoliu@zzu.edu.cn.
¹² Henan Province Research Center for Kidney Disease, Zhengzhou, China. zhangsuoliu@zzu.edu.cn.
¹³ Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China. zhangsuoliu@zzu.edu.cn.

^# Contributed equally.

PMID: 38676722
DOI: 10.1007/s00125-024-06156-x

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.

Keywords: ACSF2; Diabetic nephropathy; LC-MS/MS; Lysine lactylation; Mitochondrial dysfunction.

Abstract

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