posted on 2021-08-10, 16:28authored byBin Wang, Jing-yi Qian, Tao-tao Tang, Li-lu Lin, Nan Yu, Hong-lei Guo, Wei-jie Ni, Ling-Li Lv, Yi Wen, Zuo-Lin Li, Min Wu, Jing-Yuan Cao, Bi-Cheng Liu
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.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81720108007, 8203000544, 81670696) to Prof. Bi-Cheng Liu and Dr. Bin Wang (81700618, 82070735), and the Natural Science Foundation of Jiangsu Province (BK20181487) to Bin Wang. This research was supported by additional grants from the National Key Research Programme of Ministry of Science and Technology (2018YFC130046, 2018YFC1314000) to Bi-Cheng Liu.