Inhibitory Effects of STAT3 Transcription Factor by Synthetic Decoy ODNs on Autophagy in Renal Fibrosis.

Young-Ah Kim,Hyemin Gu,Mi-Gyeong Gwon,Hyun Jin Jung,Jaechan Leem,Seongjae Bae,Hyun-Jin An,Kwan-Kyu Park,Hyun-Ju Kim

doi:10.3390/biomedicines9040331

Abstract

Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5–12 (Atg5–12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group.

Highlights

The prevalence of chronic kidney disease (CKD) is increasing worldwide and fibrosis is responsible for chronic progressive kidney failure [1]
This study investigated the effect of signal transducer and activator of transcription 3 (STAT3) decoy ODNs on renal interstitial injury and fibrosis in ureteral obstruction (UUO) mice kidneys via hematoxylin and eosin (H&E), as well as Masson’s trichrome staining (Figure 1A)
This study showed that glomerulosclerosis and interstitial fibrosis are regulated by STAT3 decoy ODNs in a UUO mouse model

Summary

Introduction

The prevalence of chronic kidney disease (CKD) is increasing worldwide and fibrosis is responsible for chronic progressive kidney failure [1]. Renal interstitial fibrosis, characterized by the excess deposition of extracellular matrix (ECM) in the tubulointerstitium, is the final common pathway for all progressive forms of CKD, leading to end-stage renal disease [2]. Other mechanisms, such as oxidative stress, inflammation, mitochondrial damage, endoplasmic reticulum stress, and autophagy, are involved in the progression of CKD [3]. Autophagy is the cellular process of the degradation of the cytoplasmic components through the formation of autophagosomes followed by autolysosomes [8]. Phagophore form first, and expand and fuse to create

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Conclusion