Supplemental Figure 1. The average content of ZO-1 experienced an increasing trend in DN patients with the pathological progression from stage IIa to IV. The ratio of IOD of ZO-1 (A) and p62 (B) to WT-1 count in the glomeruli of DN patents at different stages as indicated.
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.<br>
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.<br>
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