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Abstract
<p class="first" id="d2297321e107">Accumulating evidence indicates that proteinuria
promotes the progression of diabetic
kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal
transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains
unclear. In our previous research, we found that miR-4756 levels were increased in
the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria.
In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial
cells, but its role has not been elucidated. Albumin stimulation significantly increased
miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated
HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We
then found that miR-4756 targeted the 3'-untranslated region (UTR) of Sestrin2 and
directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER
stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression.
Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased
5' monophosphate-activated protein kinase activation. Thus, our study provides evidence
that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting
miR-4756 may be a novel strategy for DKD treatment.
</p>