LncRNA AA465934 Improves Podocyte Injury by Promoting Tristetraprolin-Mediated HMGB1 DownRegulation in Diabetic Nephropathy

Abstract

Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.

Keywords:

• LncRNA AA465934
• diabetic nephropathy
• podocyte
• TTP
• HMGB1

Ethical approval

All experimental protocols were approved by the Ethic Committee of Zhejiang Provincial People’s Hospital(Ethics No.2020078) and comply with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Disclosure statement

The authors confirm that there are no conflicts of interest.

Authors’ contributions

Conceptualization, N. Y. and Y. Z.; methodology, N. Y., Y. Z., P. R.; software, P. R., L. Z.; validation, L. Z., D. Z. and L. F.; formal analysis, D.Z.; investigation, N. Y., Y. Z,. L. Z.; resources, D. Z.; data curation, L. Z.; writing – original draft preparation, N. Y., Y. Z.; writing – review and editing, J. J., L. F.; visualization, J. J. and N. Y.; supervision, J. J.; project administration, J. J.; funding acquisition, J. J. and L. F. All authors have read and agreed to the published version of the manuscript.

Data availability statement

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This research was supported by the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (Grant No. LHDMZ22H050001); The Key Project of Scientific Research Foundation of Chinese Medicine (2022ZZ002); the “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2023C03075); The Key project of Basic Scientific Research Operating Funds of Hangzhou Medical College (KYZD202002); Science Research Fund Project of Zhejiang Chinese Medical University (2020ZG37, 2022FSYYZY01).