Astragaloside IV represses high glucose-induced mesangial cells activation by enhancing autophagy via SIRT1 deacetylation of NF-κB P65 subunit

Abstract

AimMesangial cell (MC) activation plays an important role in many glomerular diseases associated with renal fibrosis, including diabetic kidney disease (DKD). The aim of this study was to determine whether Astragaloside IV (AS-IV) modulated MC activation in DKD via autophagy by specifically regulating the autophagy inducer sirtuin 1 (SIRT1).MethodsCultured MCs and diabetic KK-Ay mice were treated with AS-IV, and the markers and regulatory mediators of autophagy were analyzed using Western blotting, real-time PCR, ELISA and IF.ResultsAS-IV inhibited MC activation and enhanced autophagy in hyperglycemic conditions by increasing SIRT1 expression and decreasing NF-κB p65 acetylation. In addition, the SIRT1 activator SRT1720 enhanced autophagy and decreased p65 acetylation during hyperglycemia-induced MC activation. Opposite effects were seen with the SIRT1 inhibitor EX527. Furthermore, the ameliorative effect of AS-IV on MCs was abolished by the autophagy inhibitor 3-MA, while the autophagy activator rapamycin restored hyperglycemia-induced MC activation. Finally, AS-IV improved renal function and fibrosis in the diabetic KK-Ay mice.ConclusionAS-IV ameliorated renal function and morphology by inducing autophagy and inhibiting MC activation through the SIRT1-NF-κB pathway, indicating a potential therapeutic role of AS-IV in glomerular diseases.

Metformin inhibits high glucose‐induced mesangial cell proliferation, inflammation and ECM expression through the SIRT1‐FOXO1‐autophagy axis

“…Emerging studies have shown that metformin can improve the blood glucose levels of DM patients through activating AMP‐activated protein kinase (AMPK), which also activates SIRT1 and regulates energy metabolism through FOXO1 . Wang et al revealed that although high glucose reduces the SIRT1 level and increases inflammatory factor expression in mesangial cells, SIRT1 activation downregulates the transcriptional activity of nuclear factor‐kappaB (NF‐κB) and inhibits inflammatory factor production and improves the inflammatory response in the kidney …”

“…14 Wang et al 15 revealed that although high glucose reduces the SIRT1 level and increases inflammatory factor expression in mesangial cells, SIRT1 activation downregulates the transcriptional activity of nuclear factor-kappaB (NF-κB) and inhibits inflammatory factor production and improves the inflammatory response in the kidney. 15 The present work explores the role of metformin in mesangial cell proliferation, inflammation and ECM accumulation induced by high glucose and elucidates the underlying mechanism of metformin function on SIRT1/FOXO1-mediated autophagy to provide new insight into the development of DN.…”

Astragaloside IV prophylactic administration relieves recurrent allergic atopic dermatitis

“…Alterations of TLRs play a potent role in susceptibility to AD [22]. AS-IV presented a wide range of pharmacological effects through multiple pathways, however, most of them are related to TLR4-mediated NF-κB signalling pathways [8][9][10]. Therefore, we assessed several TLRs gene expression of epithelium in remission phase of AD-Re, and evaluated the effects of AS-IV on TLRs expression.…”

“…Astragaloside IV (AS-IV), a natural saponin abundant in Astragalus membranaceus, possesses multiple pharmacological effects including anti-inflammatory, anti-fibrotic, anti-tumor, neuronal and cardiac protection effects via numerous signaling pathways [3][4][5][6][7]. Accumulated evidence recently points to the important role of AS-IV in regulating Toll-like receptors (TLRs)-mediated NF-κB pathway to exert its pharmacological effects [8][9][10]. Yu-Ping-Feng-San (YPFS), a well-known traditional Chinese medicine (TCM), is clinically applied for allergic disorders with reduced relapse rates and recurring severity [11,12].…”

Silent mating‐type information regulation 2 homolog 1 overexpression is an important strategy for the survival of adapted suspension tumor cells

“…Aside from the SIRT1‐mediated inhibition of NF‐κB activity, NF‐κB signaling is also able to suppress SIRT1 activity through the expression of miRNAs as well as through an increase in ROS production . These antagonistic functions of NF‐κB and SIRT1 play several roles in inflammation and metabolism, regulation of autophagy, and neuroinflammation and cognitive impairment induced by sepsis . Therefore, the outcome of crosstalk between SIRT1, ROS, and NF‐κB should be decoded in the tumor context.…”