Complanatoside A targeting NOX4 blocks renal fibrosis in diabetic mice by suppressing NLRP3 inflammasome activation and autophagy

Ren, Chaoxing; Bao, Xiaowen; Lu, Xueliang; Du, Wei; Wang, Xiaoxuan; Wei, Jingxun; Li, Lin; Li, Xiaotian; Lin, Xin; Zhang, Qi; Ma, Bo

doi:10.1016/j.phymed.2022.154310

Cited by 20 publications

(7 citation statements)

References 54 publications

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“…Autophagy is an evolutionarily conserved catabolic pathway that degrades cytoplasmic components, moves organelles, and recycles cytoplasmic contents in eukaryotic cells, contributing to the maintenance of kidney homeostasis and function ( 7 , 8 ). As one of the most important self-protection mechanisms, basal autophagy in the kidney is critical for maintaining renal homeostasis, structure, and function ( 9 ). In acute kidney injury, autophagy is activated as an intrinsic protective mechanism in renal tubular cells ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Yang

Ling

et al. 2023

Front. Immunol.

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The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator of autophagy. Our previous studies have reported that the disorder of the PPARα/fatty acid oxidation (FAO) axis in renal tubular cells is suppressed by STAT6, which is involved in the regulation of renal fibrotic processes. Here, we found that canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO by inducing autophagy-dependent STAT6 degradation both in TGF-β1-treated HK2 cells and in unilateral ureteral occlusion (UUO) and ischemia–reperfusion (I/R) renal fibrosis mouse models. Knockdown of P62/SQSTM1 led to the impairment autophagic flux and the dysregulation of the STAT6/PPARα axis, which was confirmed by SQSTM1/P62cKO mice with UUO treatment along with bioinformatics analysis. Furthermore, SQSTM1/P62 deficiency in renal tubular cells inhibited canagliflozin’s effects that prevent FAO disorder in renal tubular cells and renal fibrosis. Mechanistically, the level of m6A eraser FTO, which interacted with SQSTM1 mRNA, decreased in the renal tubular cells both in vitro and in vivo after canagliflozin administration. Decrease in FTO stabilized SQSTM1 mRNA, which induced autophagosome formation. Collectively, this study uncovered a previously unrecognized function of canagliflozin in FTO in the autophagy modulation through the regulation of SQSTM1 mRNA stability in the renal tubular STAT6/PPARα/FAO axis and renal fibrosis.

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Section: Introductionmentioning

confidence: 99%

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Yang

Ling

et al. 2023

Front. Immunol.

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“…Although recent studies have confirmed CA exerts anti‐inflammatory effects, 20,21 the specific role of CA in TNBS‐induced colitis has not been reported. Here, we first reported that CA significantly reduced the symptoms of experimental colitis mice both in TNBS and Il‐10 −/− models, as demonstrated by elevated body weight and colon length and decreased inflammatory scores.…”

Section: Discussionmentioning

confidence: 97%

“…Complanatuside A (CA), a natural flavonoid compound extracted from the Semen Astragali Complanati, was recently reported to decrease inflammatory cytokine levels and may be a valuable candidate in ameliorating COVID‐19‐related skin inflammatory damage 20 . CA treatment hindered inflammatory gene expression and inflammasome activation by targeting nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in diabetic mice 21 . Additionally, CA displays distinct pharmacological activity in other disease models.…”

Section: Introductionmentioning

confidence: 99%

Complanatuside A ameliorates 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway

Wang,

Song,

Xia

et al. 2024

The FASEB Journal

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Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti‐inflammatory activities and our study aimed to identify its effect on TNBS‐induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS‐induced colitis, which may provide novel strategies for CD treatment.

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“…So far, many previous studies have used tubular cells to uncover the mechanism of NLRP3 inflammasome after injury [51] . Besides, the tubular cells can also be used to study the nephroprotective effects of active compounds in Chinese herbs through the pathway of NLRP3 inflammasome [52] , [53] . Moreover, our present study emphasized that the EP2 receptor is strongly expressed in response to phosphoramidon after exposure in human kidney cells from the results of IPA database analysis.…”

Section: Discussionmentioning

confidence: 99%

Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor

Huang

Lee

Sung

et al. 2023

Computational and Structural Biotechnology Journal

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Complanatoside A targeting NOX4 blocks renal fibrosis in diabetic mice by suppressing NLRP3 inflammasome activation and autophagy

Cited by 20 publications

References 54 publications

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Complanatuside A ameliorates 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway

Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor

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