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.
Highlights
Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications and the key factor that can lead to end-stage nephropathy (Perkovic et al, 2019; Ruiz-Ortega et al, 2020)
We found that FMN up-regulated the expression of Sirt1 protein in the renal tissue of db/db diabetic mice and in glomerular mesangial cells (GMCs) under the conditions of high glucose, activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway
FMN treatment caused a significant reduction in FBG levels (p < 0.01); there was no statistically significant difference between the groups treated with FMN and metformin hydrochloride (Met)
Summary
Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications and the key factor that can lead to end-stage nephropathy (Perkovic et al, 2019; Ruiz-Ortega et al, 2020). Glomerular mesangial cell proliferation, along with glomerular hypertrophy, gradually lead to the deposition of extracellular matrix (ECM) in the glomerular mesangial region. This leads to the progressive accumulation of inflammatory fibrosis components such as fibronectin (FN) and intercellular cell adhesion molecule-1 (ICAM-1), and can develop into renal fibrosis with glomerulosclerosis as the predominant feature eventually. In the pathological state of diabetes, high levels of glucose stimulates cells to produce a large number of reactive oxygen species (ROS), which activates a variety of downstream inflammatory signaling pathways, inducing and accelerating the occurrence of renal inflammatory fibrosis.
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