Long non-coding RNA lnc-CHAF1B-3 promotes renal interstitial fibrosis by regulating EMT-related genes in renal proximal tubular cells

Imai, K.; Ishimoto, Takuji; Doke, Tomohito; Tsuboi, Takayuki; Watanabe, Yu; Katsushima, Keisuke; Suzuki, Miho; Oishi, Hideto; Furuhashi, Kazuhiro; Ito, Yasuhiko; Kondo, Yutaka; Maruyama, Shoichi

doi:10.1016/j.omtn.2022.12.011

Cited by 8 publications

(3 citation statements)

References 45 publications

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“…As renal fibrosis is a common pathogenesis and pathological course in multiple CKDs, increasing evidence supports that dysfunction of renal TECs robustly contributes to renal fibrosis progression. 28,29 Hence, TECs should not only be considered a critical target of kidney injury but also a significant promoter and advocate of renal fibrosis. Therefore, targeting TECs to influence renal fibrosis may be a promising strategy for renal fibrosis prevention as well as CKD and AKI-to-CKD management.…”

Section: Discussionmentioning

confidence: 99%

“…Initially, we emphasised the characteristics and potential functions of METTL3 and m6A modifications in renal fibrosis. As renal fibrosis is a common pathogenesis and pathological course in multiple CKDs, increasing evidence supports that dysfunction of renal TECs robustly contributes to renal fibrosis progression 28,29 . Hence, TECs should not only be considered a critical target of kidney injury but also a significant promoter and advocate of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

Zhou

et al. 2023

Clinical & Translational Med

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BackgroundN6‐methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator‐mediated m6A modification during renal fibrosis and thereby explore promising anti‐renal fibrosis agents.MethodsRenal tissues from humans and mice as well as HK‐2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real‐time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase‐like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP‐like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti‐renal fibrosis.ResultsMETTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK‐2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2)‐dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7‐induced suppression of transforming growth factor‐β (TGF‐β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti‐renal fibrosis effects.ConclusionsCollectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti‐renal fibrosis agent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

Zhou

et al. 2023

Clinical & Translational Med

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“…[ 21 ] Several specifically‐expressed lncRNAs have been revealed to be involved in the regulation of RIF. [ 22,23 ] Recently, SNHG16 has been illustrated to be involved in the regulation of fibrosis and podocytes injury in diabetic nephropathy. [ 24,25 ] This work first investigated the biological function and mechanism of SNHG16 in regulating RIF by constructing a UUO‐induced RIF mouse model.…”

Section: Discussionmentioning

confidence: 99%

SNHG16/miR‐205/HDAC5 is involved in the progression of renal fibrosis

Zhao,

Wang,

Tang

et al. 2023

J Biochem & Molecular Tox

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Renal interstitial fibrosis (RIF) represents an irreversible and progressive pathological manifestation of chronic renal disease, which ultimately leads to end‐stage renal disease. Long noncoding RNAs (lncRNAs) have been suggested to be involved in the progression of RIF. Small nucleolar RNA host gene 16 (SNHG16), a member of lncRNAs, has been found to be involved in the progression of pulmonary fibrosis. This paper first researched the effect of SNHG16 on renal fibrosis. We established a unilateral ureteral obstruction (UUO)‐induced mouse RIF model by ligation of the left ureter to evaluate the biological function of SNHG16 in RIF. As a result, SNHG16 was upregulated in UUO‐induced renal fibrotic tissues. Knockdown of SNHG16 inhibited RIF and reduced alpha‐smooth muscle actin (α‐SMA), fibronectin, and college IV expression. miR‐205 was a target of SNHG16, and downregulated in UUO‐induced renal fibrotic tissues. Inhibition of miR‐205 promoted RIF and increased the expression of α‐SMA, college IV, and fibronectin. Overexpression of SNHG16 promoted the UUO‐induced RIF, but miR‐205 abrogated this effect of SNHG16. Histone deacetylase 5 (HDAC5) showed high expression in UUO‐induced renal fibrotic tissues. Knockdown of HDAC5 significantly reduced α‐SMA, fibronectin, and college IV expression in renal tissues of UUO‐induced mice. Inhibition of miR‐205 promoted HDAC5 expression, but knockdown of SNHG16 inhibited HDAC5 expression in renal tissues of UUO‐induced mice. In conclusion, SHNG16 is highly expressed in renal fibrotic tissues of UUO‐induced mice. Knockdown of SHNG16 may prevent UUO‐induced RIF by indirectly upregulating HDAC5 via targeting miR‐205. SHNG16 may be novel target for treating renal fibrosis.

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Necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl3-induced kidney damage

Zhang

et al. 2023

Food and Chemical Toxicology

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Long non-coding RNA lnc-CHAF1B-3 promotes renal interstitial fibrosis by regulating EMT-related genes in renal proximal tubular cells

Cited by 8 publications

References 45 publications

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

SNHG16/miR‐205/HDAC5 is involved in the progression of renal fibrosis

Necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl3-induced kidney damage

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