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Exp Clin Endocrinol Diabetes 2020; 128(09): 599-606
DOI: 10.1055/a-1069-7290
Article

Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy

Le Li
1   Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
,
Lei Tang
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
3   Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
,
Xiaoping Yang
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
4   Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, China
,
Ruifang Chen
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
,
Zhen Zhang
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
,
Yiping Leng
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
,
Alex F. Chen
1   Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
2   The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
5   Department of Cardiology, and Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
› Author Affiliations Funding: This work was supported, in part, by the National Science Foundation of China (NSFC) Projects 81930012 and 81730013, and the Chinese Postdoctoral Science Foundation 2018M643010.
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Abstract

Background and Aims The inflammation of glomerular endothelial cells induces and promotes the activation of macrophages and contributes to the development of diabetic nephropathy. Thus, this study aimed to investigate the gene regulatory effect and potential role of pyruvate kinase M2 (PKM2) in inflammatory response in diabetic nephropathy.

Methods The plasma PKM2 levels of patients with diabetes were evaluated. Eight-week-old mice were divided into three groups (WT, db/db mice, and db/db mice treated with TEPP-46) and raised for 12 weeks. Blood and kidney samples were collected at the end of the experiment. Endothelial cells were stimulated with high glucose with or without TEPP-46. The expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), phospho-PKM2, PKM2, phospho-STAT3(signal transducer and activator of transcription), STAT3, nuclear factor kappa B (NF-kB), and phospho-NF-kB in vivo and in vitro were determined using Western blot. The activation of macrophages (CD68+CD86+) in the glomeruli was assessed via fluorescent double staining. Moreover, immune endothelial adhesion experiments were performed.

Results The plasma PKM2 levels of patients with type 2 diabetes increased. P-PKM2 was up-regulated in vivo and in vitro. TEPP-46 decreased inflammatory cell infiltration and ICAM-1 expression in vivo and in vitro and inhibited the differentiation of macrophages to M1 cells in db/db mice with diabetic nephropathy. PKM2 regulated the phosphorylation of STAT3 and NF-kB. Furthermore, high glucose levels induced the transition from tetramer to dimer and the nuclear translocation of PKM2.

Conclusion The gene regulatory effect of PKM2 is involved in renal inflammation in type 2 diabetic nephropathy by promoting the phosphorylation of STAT3 and NF-kB and the expression of intercellular adhesion molecule 1. Thus, the down-regulation of phosphorylated PKM2 may have protective effects against diabetic nephropathy by inhibiting renal inflammation.

Key words

PKM2 - gene regulatory effects - type 2 diabetic nephropathy - renal inflammation - ICAM-1

Supplementary Material



Publication History

Received: 19 April 2019
Received: 31 October 2019

Accepted: 25 November 2019

Article published online:
20 January 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

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