Dr Qiyu Yue1,2, Dr Chen Yong2,3, Dr Weiwei Tao4, Dr Enchao Zhou1,2,3
1 The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China, 2Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China, 3Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China, 4School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Biography:
Qiyu Yue: Nanjing University of Traditional Chinese Medicine, master’s candidate at Jiangsu Province Hospital of Traditional Chinese Medicine
Research direction:
TCM clinical and basic research on kidney diseases
A total of 5 papers were published, of which the first author published 2 papers, and the first host won the special prize in the “Challenge Cup” National Extracurricular Science and Technology Works Competition.
Background:
Astragaloside IV (AS-IV), a major bioactive component purified from Astragalus membranaceus (Fisch.) Bunge, has demonstrated efficacy in reducing hyperglycemia, ameliorating proteinuria, and attenuating renal tubular damage in preclinical diabetic nephropathy (DN) models.
Aim:
This study tests whether AS-IV protects against DN by activating SIRT6-dependent epigenetic pathway.
Methods:
DN was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). MPC5 cell line was selected in cell experiment. The kidney function parameters were evaluated, and the histomorphology of glomerular tissues was examined. Molecular docking was used to confirm that AS-IV was able to directly bind to SIRT6, and then furtherly explored the downstream regulation mechanism related to podocyte autophagy and apoptosis by immunofluorescence staining, Quantitative Real-Time PCR, and western blotting assays. Chromatin Immunoprecipitation was used to detect whether histone H3K9ac was indeed able to bind to the notch1 promoter region. SIRT6 knockdown was used to confirm its role in AS-IV’s podocyte protection.
Results:
This study discovered that AS-IV might alleviate renal biochemical and pathological damage and podocyte injury in mice modeled by STZ. Molecular docking reveals that AS-IV directly binds to SIRT6, which was previously believed to be its target. SIRT6 deacetylates histone H3K9 to prevent Notch1 transcription. Subsequent research showed that the protective benefits of AS-IV against damage in HG-stimulated podocytes were diminished when SIRT6 was depleted.
Conclusion:
AS-IV protects podocytes in DN mice both in vitro and in vivo by activating the SIRT6/Notch1 pathway, which mediates autophagy regulation and reduces apoptosis.
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