Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury

Jung, Hyun Jin; An, Hyun‐Jin; Gwon, Mi‐Gyeong; Gu, Hyemin; Bae, Seongjae; Lee, Sun Jae; Kim, Young-Ah; Leem, Jaechan

doi:10.3390/molecules27030766

Cited by 7 publications

(8 citation statements)

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“…However, injection of the autophagy inhibitor ODN significantly decreased the expression of Beclin1 and LC3 and reduced the expression of renal fibrosis marker proteins. This suggests that by inhibiting autophagy, renal fibrosis can be attenuated (Wu et al, 2021;Jung et al, 2022). In the UUO rat model, rats were executed on days 3, 7, and 14 after modeling, and time-dependent induction of autophagy was found in both the obstructed and contralateral unobstructed kidneys, and sustained activation of autophagy led to tubular apoptosis and renal fibrosis, whereas the autophagy inhibitor 3-methyladenine (3-MA) inhibited sustained autophagy-induced tubular apoptosis and renal fibrosis (Kim et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Tian

Pan

et al. 2022

Front. Pharmacol.

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Renal fibrosis is a common pathway for the progression of various chronic kidney diseases (CKD), and the formation and deterioration will eventually lead to end-stage renal failure, which brings a heavy medical burden to the world. HeidihuangWan (HDHW) is a herbal formulation with stable and reliable clinical efficacy in the treatment of renal fibrosis. However, the mechanism of HDHW in treating renal fibrosis is not clear. In this study, we aimed to investigate the mechanism of HDHW to improve renal fibrosis. Wistar rats were randomly divided into the normal control group, 5/6 Nephrectomy group, astragaloside IV (AS-IV) group, HDHW group, and HDHW + IGF-1R inhibitor (JB1) group. Except for the normal control group, the rat renal fibrosis model was established by 5/6 nephrectomy and intervened with drugs for 8 weeks. Blood samples were collected to evaluate renal function. Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), Modified Masson’s Trichrome (Masson) staining were used to evaluate the pathological renal injury, and immunohistochemistry and Western blotting were used to detect the protein expression of renal tissue. The results showed that HDHW was effective in improving renal function and reducing renal pathological damage. HDHW down-regulated the levels of fibrosis marker proteins, including α-smooth muscle actin (α-SMA), vimentin, and transforming growth factors–β(TGF-β), which in turn reduced renal fibrosis. Further studies showed that HDHW down-regulated the expression of autophagy-related proteins Beclin1 and LC3II, indicating that HDHW inhibited autophagy. In addition, we examined the activity of the class I phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway, an important signaling pathway regulating autophagy, and the level of insulin-like growth factor 1 (IGF-1), an upstream activator of PI3K/Akt/mTOR. HDHW upregulated the expression of IGF-1 and activated the PI3K/Akt/mTOR pathway, which may be a vital pathway for its inhibition of autophagy. Application of insulin-like growth factor 1 receptor (IGF-1R) inhibitor further confirmed that the regulation of autophagy and renal fibrosis by HDHW was associated with IGF-1-mediated activation of the PI3K/Akt/mTOR pathway. In conclusion, our study showed that HDHW inhibited autophagy by upregulating IGF-1 expression, promoting the binding of IGF-1 to IGF-1R, and activating the PI3K/Akt/mTOR signaling pathway, thereby reducing renal fibrosis and protecting renal function. This study provides support for the application and further study of HDHW.

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Section: Discussionmentioning

confidence: 99%

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Tian

Pan

et al. 2022

Front. Pharmacol.

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“…The injured site of the renal interstitium can be rapidly infiltrated by a large number of inflammatory cells, aggravating fibrosis [ 19 ]. After prolonged renal injury, the infiltrated inflammatory cells release excessive pro-inflammatory cytokines, such as tumor necrosis factor (TNF) -α, interleukin (IL)-1β and IL-6, to clean up tissue debris, dead cells, and invading organisms from the injured site, as well as pro-fibrotic cytokines and growth factors [ 6 , 21 , 22 , 23 ]. Once renal fibrosis develops, most patients progress to irreversible end-stage renal disease, in which kidney transplantation with dialysis is the only therapeutic option [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, the relationship between autophagy and renal fibrosis has been reported in studies on renal inflammation and autophagy [ 22 , 24 , 34 ]. Autophagy is an important cellular mechanism for the intracellular lysosome-mediated degradation of damaged organelles, protein aggregates, and other macromolecules in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

“…Lysosomes fuse with phagosomes to degrade their contents, contributing to lysosomal membrane permeabilization [ 37 , 38 ]. Autophagy is involved in renal diseases including acute kidney injury, glomerular diseases, and TIF [ 22 ]. Despite emerging evidence suggesting that autophagy occurs during renal TIF, the role of autophagy activation in fibrosis and the mechanism by which autophagy influences fibrosis remain controversial.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Fibrotic Effect of Synthetic Noncoding Decoy ODNs for TFEB in an Animal Model of Chronic Kidney Disease

Lee

Kim

Park

2022

IJMS

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Despite emerging evidence suggesting that autophagy occurs during renal interstitial fibrosis, the role of autophagy activation in fibrosis and the mechanism by which autophagy influences fibrosis remain controversial. Transcription factor EB (TFEB) is a master regulator of autophagy-related gene transcription, lysosomal biogenesis, and autophagosome formation. In this study, we examined the preventive effects of TFEB suppression on renal fibrosis. We injected synthesized TFEB decoy oligonucleotides (ODNs) 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 (IL)-1β, tumor necrosis factor-α (TNF-α), and collagen was decreased by TFEB decoy ODN. Additionally, TEFB ODN administration inhibited the expression of microtubule-associated protein light chain 3 (LC3), Beclin1, and hypoxia-inducible factor-1α (HIF-1α). We confirmed that TFEB decoy ODN inhibited fibrosis and autophagy in a UUO mouse model. The TFEB decoy ODNs also showed anti-inflammatory effects. Collectively, these results suggest that TFEB may be involved in the regulation of autophagy and fibrosis and that regulating TFEB activity may be a promising therapeutic strategy against kidney diseases.

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“…In the state of myocardial ischemia and energy deficiency, mTORC1 could be inhibited [ 13 ]. Then, the level of cardiomyocyte autophagy is upregulated, and cardiomyocyte death is reduced [ 14 ]. Some studies have proved that the AMPK pathway can directly or indirectly regulate mTORC1 in ischemic state and finally cause the upregulation of autophagy level and protect myocardium.…”

Section: Introductionmentioning

confidence: 99%

Improvement of Myocardial Cell Injury by miR-199a-3p/mTOR Axis through Regulating Cell Apoptosis and Autophagy

Chen

et al. 2022

Journal of Immunology Research

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Background. Myocardial ischemia-reperfusion injury (MIRI) is characterized by its high incidence rate and mortality. miR-199a-3p is thought to be strongly linked with the development of some myocardial diseases, but the influence of miR-199a-3p in MIRI remains unclear. Methods. AC16 cells were used. The concentrations of mammalian target of rapamycin (mTOR), light chain 3 II/light chain 3 I, and Beclin-1 were detected with western blotting and qRT-PCR. The binding site between mTOR and miR-199a-3p was evaluated via luciferase report assay. Cell apoptosis was evaluated through flow cytometry. Results. Knockdown of miR-199a-3p accelerated the myocardial cell injury after L-oxygen treatment. Increased expression of mTOR and suppressed autophagy were observed after knockdown of miR-199a-3p. Knockdown of miR-199a-3p or overexpression of mTOR greatly aggravated cell injury through inhibiting autophagy. Conclusions. This study might be helpful for the therapeutic method of MIRI through by regulating miR-199a-3p/mTOR.

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Anti-Fibrotic Effect of Synthetic Noncoding Oligodeoxynucleotide for Inhibiting mTOR and STAT3 via the Regulation of Autophagy in an Animal Model of Renal Injury

Cited by 7 publications

References 86 publications

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Anti-Fibrotic Effect of Synthetic Noncoding Decoy ODNs for TFEB in an Animal Model of Chronic Kidney Disease

Improvement of Myocardial Cell Injury by miR-199a-3p/mTOR Axis through Regulating Cell Apoptosis and Autophagy

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