Herbs And Phytochemicals: Tiliroside From the Herb Potentilla Chinensis Is A Natural Nrf2 Activator That Helps With Diabetic Nephropathy
Herbs And Phytochemicals
: Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus, characterized by proteinuria and progressive renal function deterioration. Despite the use of anti-hyperglycemic and anti-hypertensive medications, there are limited therapeutic options available for Diabetic nephropathy (DN). This lack of effective treatments often leads to end-stage renal disease, requiring dialysis or kidney transplantation. Therefore, finding novel therapeutic approaches for DN is of paramount importance.
The pathogenesis of diabetic nephropathy (DN) involves high glucose levels and abnormal metabolism, leading to oxidative stress caused by the overproduction of reactive oxygen species (ROS) that overwhelms the body's ability to neutralize them. Oxidative stress, in turn, triggers the excessive secretion of transforming growth factor β1 (TGF-β1), a key fibrotic factor. TGF-β1 promotes the synthesis of extracellular matrix (ECM) proteins like collagen IV, fibronectin, and laminin, contributing to the thickening of the basement membrane and mesangial expansion. If left unchecked, this process ultimately results in glomerular hypertrophy, renal fibrosis, and, ultimately, end-stage renal disease.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a crucial role in protecting cells against oxidative stress. It regulates the expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Under normal conditions, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap1) in the cytosol, leading to Nrf2 degradation. When exposed to oxidants or electrophiles, the interaction between Keap1 and Nrf2 is disrupted, allowing Nrf2 to translocate to the nucleus and activate antioxidant genes, ultimately reducing oxidative stress.
Phytochemicals found in various plants have been shown to activate Nrf2, providing potential treatments for oxidative stress-related diseases, including Diabetic nephropathy (DN).
Tiliroside is a dietary glycosidic flavonoid found in several plants, including Potentilla chinensis. Previous studies have demonstrated that tiliroside has antioxidant and anti-inflammatory properties and can activate Nrf2 in different cell types. These properties make tiliroside a promising candidate for diabetic nephropathy (DN) treatment. In this Herbs And Phytochemicals
study, researchers from Xuzhou Medical University explored the effects of tiliroside from Potentilla chinensis on mesangial cells exposed to high glucose conditions, mimicking the environment of diabetic nephropathy (DN).
-Tiliroside Inhibits Mesangial Cell Proliferation Induced by High Glucose:
The researchers found that tiliroside did not affect the survival of normal mesangial cells. However, when exposed to high glucose, mesangial cells exhibited self-limited proliferation, which was significantly inhibited in the presence of tiliroside. This inhibition of cell proliferation by tiliroside suggested its potential as a therapeutic agent for DN.
-Tiliroside Ameliorates Oxidative Stress:
High glucose levels resulted in the overproduction of ROS in mesangial cells, which led to oxidative stress. Tiliroside effectively reduced ROS production and decreased the levels of malondialdehyde (MDA), a marker of oxidative stress. Additionally, the activity of antioxidant enzymes, including SOD, CAT, and GPx, was reduced by high glucose, but tiliroside treatment significantly increased their activity. These findings indicated that tiliroside could mitigate oxidative stress in mesangial cells exposed to high glucose.
-Tiliroside Attenuates ECM Accumulation:
High glucose stimulation led to the overproduction of TGF-β1 in mesangial cells, which subsequently elevated the secretion of connective tissue growth factor (CTGF) and the synthesis of ECM proteins, such as collagen IV, fibronectin, and laminin. Tiliroside treatment significantly reduced the levels of TGF-β1, CTGF, and ECM proteins, suggesting its ability to prevent ECM accumulation in mesangial cells.
-Tiliroside Activates Nrf2:
To understand the mechanisms underlying the effects of tiliroside, the researchers investigated its impact on Nrf2 activation in mesangial cells. They observed that tiliroside increased the levels of both total and nuclear Nrf2. A dual luciferase reporter assay demonstrated that tiliroside enhanced Nrf2's binding to the antioxidant response elements (ARE) in the promoters of target genes, leading to the upregulation of genes like HO-1 and NQO1, both of which are downstream targets of Nrf2.
-Nrf2 Activation Is Necessary for Tiliroside's Effects:
To confirm the role of Nrf2 activation in the effects of tiliroside, the researchers used siRNA interference to knock down Nrf2. In cells where Nrf2 was knocked down, tiliroside was unable to suppress ROS and MDA production effectively, suggesting that the antioxidant effects of tiliroside are closely associated with Nrf2 activation. Similarly, the reduction in ECM accumulation induced by tiliroside was less pronounced in cells with Nrf2 knockdown, indicating that Nrf2 activation is integral to tiliroside's effects.
-Tiliroside Activates Nrf2 in a Keap1-Dependent Manner:
The researchers conducted co-immunoprecipitation assays to elucidate how tiliroside activates Nrf2. They found that tiliroside disrupted the interaction between Keap1 and Nrf2, leading to the release of Nrf2 from Keap1. Molecular docking studies provided insights into the interactions between tiliroside and key amino acid residues in the Nrf2 binding cavity of Keap1, which supported the hypothesis that tiliroside acts as an electrophile and reacts with critical cysteine residues on Keap1, preventing Nrf2 degradation and promoting its nuclear translocation.
Diabetic nephropathy (DN) is a severe and devastating complication of diabetes, leading to substantial morbidity and mortality. Current treatment strategies focus on strict control of blood glucose and blood pressure levels. High glucose levels in the early stages of DN stimulate the self-limited proliferation of mesangial cells, followed by the inhibition of proliferation due to excessive secretion of TGF-β1. This, in turn, leads to ECM accumulation and glomerular hypertrophy. The study found that tiliroside could effectively inhibit the proliferation of mesangial cells stimulated by high glucose, providing a potential strategy for preventing this early stage of diabetic nephropathy (DN).
Oxidative stress is a significant factor in diabetic nephropathy (DN) pathogenesis, as it is triggered by high glucose levels and leads to further complications.
Tiliroside was found to reduce oxidative stress by decreasing ROS and MDA levels while increasing the activity of antioxidant enzymes such as SOD, CAT, and GPx in mesangial cells.
Renal fibrosis, a hallmark of diabetic nephropathy (DN), is closely linked to TGF-β1, which promotes ECM protein synthesis. Tiliroside was shown to suppress the secretion of TGF-β1 and CTGF and reduce the levels of ECM proteins, suggesting its potential in preventing renal fibrosis.
Nrf2 activation is a promising approach to combat oxidative stress-related diseases, including diabetic nephropathy (DN). Tiliroside's ability to activate Nrf2 and enhance the transcription of Nrf2 target genes such as HO-1 and NQO1 was demonstrated in the study. The findings also confirmed that Nrf2 activation was necessary for tiliroside's effects against oxidative stress and ECM accumulation.
The interaction between Nrf2 and Keap1 is central to the regulation of Nrf2 activity. Tiliroside's ability to disrupt this interaction was shown through co-immunoprecipitation and molecular docking studies, highlighting the Keap1-dependent mechanism through which tiliroside activates Nrf2.
In conclusion, the study identified tiliroside from Potentilla chinensis as a promising natural compound for the treatment of diabetic nephropathy (DN). Tiliroside demonstrated its ability to inhibit mesangial cell proliferation, reduce oxidative stress, and attenuate ECM accumulation in mesangial cells exposed to high glucose. These effects were closely associated with the activation of Nrf2 and the disruption of the Keap1-Nrf2 complex by tiliroside. These findings provide valuable insights into the development of natural Nrf2 activators and phytochemical-based treatments for diabetic nephropathy (DN), offering hope for improved management of this severe diabetic complication.
The study findings were published in the peer reviewed Journal of Functional Foods.
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