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.
Overview
- The study investigates the role of LncRNA AA465934 in high glucose (HG)-mediated podocyte injury and diabetic nephropathy (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. The primary objective of the study is to determine the role of AA465934 in HG-mediated podocyte injury and DN and to identify potential therapeutic avenues for managing these conditions.
Comparative Analysis & Findings
- The study found that AA465934 improved DN progression and podocyte damage in T2DN mice. 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. The key findings of the study suggest that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study identifies a potential therapeutic avenue for managing podocyte injury and DN. The findings suggest that the AA465934/TTP/HMGB1/autophagy axis could be targeted for the treatment of these conditions. However, the study has limitations, such as the use of a spontaneous T2DN model, which may not fully capture the complexity of human DN. Future research should address these limitations and explore the potential of this therapeutic avenue in human subjects. Possible future research directions include the development of small molecule inhibitors of TTP-PIM2 binding or the use of autophagy inducers to enhance the therapeutic effects of AA465934.