Formononetin Activates the Nrf2/ARE Signaling Pathway Via Sirt1 to Improve Diabetic Renal Fibrosis

Abstract

Oxidative stress is the main factor responsible for the induction of diabetic renal fibrosis. Thus, improving the state of oxidative stress can effectively prevent the further deterioration of diabetic nephropathy (DN). Previous research has shown that formononetin (FMN), a flavonoid with significant antioxidant activity and Sirt1 activation effect, can improve diabetic renal fibrosis. However, the exact mechanisms underlying the effect of FMN on diabetic renal fibrosis have yet to be elucidated. In this study, we carried out in vivo experiments in a db/db (diabetic) mouse model and demonstrated that FMN activated the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway and improved oxidative stress by increasing levels of sirtuin-1 (Sirt1) protein level in renal tissue. We also found that this process reversed the up-regulation of fibronectin (FN) and intercellular adhesion molecule 1 (ICAM-1) and led to an improvement in renal insufficiency. In vitro results further showed that FMN significantly reversed the upregulation of FN and ICAM-1 in glomerular mesangial cells (GMCs) exposed to high glucose. FMN also promoted the expression of Nrf2 and widened its nuclear distribution. Thus, our data indicated that FMN inhibited hyperglycemia-induced superoxide overproduction by activating the Nrf2/ARE signaling pathway. We also found that FMN up-regulated the expression of Sirt1 and that Sirt1 deficiency could block the activation of the Nrf2/ARE signaling pathway in GMCs induced by high glucose. Finally, we found that Sirt1 deficiency could reverse the down-regulation of FN and ICAM-1 induced by FMN. Collectively, our data demonstrated that FMN up-regulated the expression of Sirt1 to activate the Nrf2/ARE signaling pathway, improved oxidative stress in DN to prevent the progression of renal fibrosis. Therefore, FMN probably represents an efficient therapeutic option of patients with DN.

MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

“…SIRT1 is a NAD + sensitive deacetylase that is associated with lifespan and is believed to have beneficial effects on counter aging [ 46 ]. In addition to ameliorating insulin assistance, SIRT1 has also been known to promote the activation of the Nrf-2/ARE pathway and improve oxidative stress in diabetic nephropathy [ 47 ]. Increasing the total level and nuclear activity of SIRT1 could reduce the expression of caspase-3 and Bax and increase SOD and GSH levels in doxorubicin-induced nephropathy [ 48 ].…”

Network Pharmacology Combined with Bioinformatics to Investigate the Mechanisms and Molecular Targets of Astragalus Radix-Panax notoginseng Herb Pair on Treating Diabetic Nephropathy

“…Formononetin possesses multiple biological activities, such as antioxidant, anti-inflammatory, and regulating immune responses [ 61 , 62 ]. Formononetin improved oxidative stress and prevented the progression of renal fibrosis in DN by activating the Nrf2/ARE signaling pathway [ 43 ]. Experimental studies have shown that isorhamnetin has renoprotective effects on DN through improving fasting blood glucose, increasing autophagosomes in renal tissues, and suppressing miRNA regulation of autophagy genes [ 44 ].…”

“…Molecular docking, a method of analyzing the binding site and affinity between the conformation of molecules and macromolecular targets, has been considered a crucial technique for structure-based drug discovery [ 40 ]. The core DN-related genes targeted by the AR-PN herb pair bioactive components was identified according to the component-target-pathway network, which were further validated by molecular docking with the experimentally verified AR-PN herb pair bioactive components possessing renoprotective effects on DN, including quercetin [ 41 ], kaempferol [ 42 ], formononetin [ 43 ], and isorhamnetin [ 44 ]. First, the mol2 formats of these bioactive components were obtained from the TCMSP database and PubChem database, which were converted to the format of pdb and pdbqt via Pymol software and AutoDock Tools 1.5.6, respectively.…”

Potential of Polyphenols to Restore SIRT1 and NAD+ Metabolism in Renal Disease

“…Treatment of the mesangial cells with AGEs reduced SIRT1 protein expression and activity but induced the overproduction of fibronectin and TGF-β1 levels in a dose- and time-dependent manner. SIRT1 upregulates the expression of NRF2 and activates the antioxidant response element (ARE) antioxidative pathway to prevent the progression of renal fibrosis [ 69 , 215 ]. The expression of proinflammatory and profibrotic cytokines in vitro and in vivo was reported in the HBZY-1 rat glomerular mesangial cell line treated continuously in a high-glucose milieu and in a diabetic mouse model.…”