VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-mediated Autophagy Pathway in Diabetic Nephropathy
| Autor: | Nan Yu, Ling-Li Lv, Hong-lei Guo, Jing-Yi Qian, Jing-Yuan Cao, Tao-Tao Tang, Zuo-Lin Li, Bi-Cheng Liu, Yi Wen, Min Wu, Bin Wang, Lilu Lin, Wei-jie Ni |
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| Rok vydání: | 2021 |
| Předmět: |
Endocrinology
Diabetes and Metabolism Kidney Glomerulus Autophagy-Related Proteins Down-Regulation Kidney Calcitriol receptor Tight Junctions Rats Sprague-Dawley Diabetic nephropathy Mice Random Allocation Mice Inbred NOD Diabetes mellitus Autophagy Internal Medicine medicine Animals Humans Diabetic Nephropathies Cells Cultured Caspase 8 Bone Density Conservation Agents Tight junction Caspase 3 Podocytes Chemistry digestive oral and skin physiology RNA-Binding Proteins medicine.disease Rats Cell biology Gene Expression Regulation Ergocalciferols Ubiquitin-Conjugating Enzymes Zonula Occludens-1 Protein Slit diaphragm Albuminuria Receptors Calcitriol medicine.symptom Flux (metabolism) |
| DOI: | 10.2337/figshare.15108672 |
| Popis: | Foot process effacement is an important feature of early diabetic nephropathy (DN) which is closely related to the development of albuminuria. Under certain nephrotic conditions, the integrity and function of the glomerular slit diaphragm (SD) structure were impaired and replaced by the tight junction (TJ) structure, resulting in so-called SD-TJ transition, which could partially explain the effacement of foot processes at the molecular level. However, the mechanism underlying the SD-TJ transition has not been described in DN. Here, we demonstrated that impaired autophagic flux blocked p62 mediated degradation of ZO-1 (TJ protein) and promoted podocytes injury via activation of caspase 3 and caspase 8. Interestingly, the expression of VDR in podocytes was decreased under diabetic condition which impaired autophagic flux through down-regulating Atg3. Of note, we also found that VDR abundance was negatively associated with impaired autophagic flux and SD-TJ transition in the glomeruli from human renal biopsy samples with DN. Furthermore, VDR activation improved autophagic flux and attenuated SD-TJ transition in the glomeruli of diabetic animal models. In conclusion, our data provided the novel insight that VDR/Atg3 axis deficiency resulted in SD-TJ transition and foot processes effacement via blocking p62-mediated autophagy pathway in DN. |
| Databáze: | OpenAIRE |
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