Diabetic nephropathy (DN) is a grave complication of diabetes mellitus, imposing a significant health and economic burden. The hallmark of DN is characterized by proteinuria and progressive renal function impairment.
Despite the use of anti-hyperglycemic and anti-hypertensive agents, there remains a lack of truly effective therapeutic strategies for DN, often necessitating dialysis or kidney transplantation in end-stage cases. Therefore, the imperative to discover novel treatments for DN cannot be overstated.
This article delves into the intricate pathogenesis of DN, where high glucose levels and their aberrant metabolism induce oxidative stress by generating excessive reactive oxygen species (ROS). These ROS disrupt the delicate balance between their production and consumption, exacerbating the oxidative stress in diabetic patients.
The upshot of this oxidative stress is the excessive secretion of transforming growth factor β1 (TGF-β1), a pivotal fibrotic factor, which subsequently triggers the synthesis of extracellular matrix proteins such as collagen IV, fibronectin, and laminin through various pathways.
The continuous accumulation of extracellular matrix, coupled with the self-limited proliferation of mesangial cells prompted by high glucose levels, leads to mesangial expansion and thickening of the basement membrane. If not intervened in a timely manner, glomerular hypertrophy and renal fibrosis ensue, eventually culminating in glomerulosclerosis and end-stage renal disease.
Nuclear factor erythroid 2-related factor 2 (Nrf2) emerges as a promising player in the battle against DN.
Nrf2 is a transcription factor that regulates the expression of target genes encoding essential antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and more.
In non-stress conditions, Nrf2 is sequestered by Kelch-like ECH-associated protein 1 (Keap1) in the cytosol, which promotes its ubiquitination and subsequent degradation.
However, when the cellular environment becomes oxidative or electrophilic, Keap1’s grip on Nrf2 loosens, allowing Nrf2 to translocate into the nucleus. In the nucleus, Nrf2 enhances the transcription of target genes by binding to the antioxidant response elements (ARE) regions on their promoters. Activating Nrf2 is a potent strategy to mitigate oxidative stress-related diseases, including DN.
Phytochemicals have emerged as valuable candidates for activating Nrf2. Several phytochemicals found in vegetables and fruits, such as sulforaphane and cinnamic aldehyde, have been shown to attenuate DN by activating Nrf2.
In this context, tiliroside, a dietary glycosidic flavonoid found in various plants, including Potentilla grandiflora and Potentilla nepalensis, is a notable contender. Previous studies have indicated tiliroside’s potential in addressing various health issues, including ulcerative colitis, metabolic disorders, cancer cell growth inhibition, and the inhibition of α-glucosidase.
In diabetic rats, tiliroside extracted from Potentilla chinensis exhibited anti-hyperglycemic, anti-hyperlipidemic, and antioxidant effects, providing a solid foundation for exploring its impact on DN.
Moreover, tiliroside has demonstrated neuroprotective effects against neuroinflammation and neurotoxicity by activating Nrf2, further underlining its potential as an Nrf2 activator. The convergence of evidence has led to the investigation of tiliroside as a natural Nrf2 activator for DN treatment. Using an in vitro model involving human mesangial cells under high glucose conditions, this study explores the effects of tiliroside and the underlying mechanisms.
Diabetic nephropathy (DN) is a debilitating complication of diabetes, contributing significantly to morbidity and mortality. Due to the concept of metabolic memory, the conventional approach of strict blood pressure and glucose control in clinical settings has limited effectiveness in preventing the progression of DN.
At the early stages of DN, high glucose levels induce the self-limited proliferation of mesangial cells, initially promoting proliferation and later inhibiting it due to the excessive secretion of TGF-β1. Simultaneously, high glucose triggers the accumulation of extracellular matrix (ECM), a process that, when coupled with cell proliferation, results in glomerular hypertrophy.
In this context, tiliroside, derived from Potentilla chinensis, demonstrates inhibitory effects on mesangial cell proliferation induced by high glucose. This effect is particularly crucial in halting the initial stages of DN, preventing glomerular hypertrophy, and mitigating the development of the condition.
Oxidative stress plays a central role in the pathogenesis of DN, serving as a mediator of glucose signaling. The excessive generation of reactive oxygen species (ROS) stems from the monoelectric reduction of molecular oxygen, leading to the formation of the superoxide radical anion. This anion can be converted to hydrogen peroxide with the aid of superoxide dismutase (SOD). Hydrogen peroxide is then decomposed to water with the involvement of catalase (CAT) or glutathione peroxidase (GPx).
Tiliroside demonstrates its efficacy by suppressing the increase of ROS and malondialdehyde (MDA) and enhancing the levels of SOD, CAT, and GPx in mesangial cells exposed to high glucose. This indicates that tiliroside effectively mitigates oxidative stress, a crucial factor in DN development.
Renal fibrosis is a defining feature in the progression of DN, contributing to the loss of normal tissue structure. This fibrosis is closely linked to TGF-β1, a factor up-regulated by ROS, which in turn promotes the abnormal secretion of ECM proteins. Connective tissue growth factor (CTGF), a downstream mediator of TGF-β1, stimulates the accumulation of mesangial ECM, exacerbating the profibrotic activity in DN.
Tiliroside emerges as an effective combatant against renal fibrosis by suppressing the excessive secretion of TGF-β1 and CTGF in mesangial cells exposed to high glucose. This leads to a blockage in the synthesis of ECM proteins, addressing one of the central pathological mechanisms driving DN.
Nrf2, as a pivotal transcription factor, contributes to cellular defense by regulating the transcription of target genes encoding essential antioxidant enzymes, both direct and indirect. While persistent Nrf2 activation may exacerbate toxicity in certain cases, it remains a promising therapeutic target for oxidative stress-associated diseases.
The structure of the Keap1-Nrf2 complex has revealed the interaction between Keap1 and Nrf2. In this complex, two Keap1 monomers are connected in their BTB domains, forming a homodimer. This homodimer interacts with the “degrons” of Nrf2, which include DLG and ETGE motifs. Of particular interest is the interaction between Keap1 and Nrf2, where the affinity of DLG to the Kelch domain is lower than ETGE. This led to the “hinge and latch” model, elucidating how Nrf2 binds to Keap1.
Tiliroside’s activation of Nrf2 is Keap1-dependent, as indicated by co-immunoprecipitation assays. Molecular docking analysis reveals that tiliroside occupies the Nrf2 binding cavity by interacting with key amino acid residues in subpockets, including P1 (Ser508), P2 (Ser363), P3 (Ser602), and P4 (Ser555). Furthermore, tiliroside, with its moieties of flavonoid and coumaric acid, contains α,β-unsaturated ketone substructures, indicating its potential as an electrophile that reacts with key cysteine residues of Keap1. This interaction potentially contributes to Nrf2 activation.
Additionally, tiliroside’s phenolic compounds can act as typical ROS scavengers, enhancing its antioxidant effects by reacting with ROS molecules. This dual role of tiliroside in targeting oxidative stress through Nrf2 activation and ROS scavenging reinforces its potential as a promising therapeutic option for DN.
Diabetic nephropathy (DN) presents a formidable challenge in the realm of diabetic complications, with significant consequences for patients’ health and healthcare costs. The pathogenesis of DN is complex, driven by factors such as oxidative stress, abnormal ECM production, and uncontrolled mesangial cell proliferation. While conventional treatments have been limited in their effectiveness, the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a promising avenue for potential therapies.
Tiliroside, a phytochemical derived from various plants, has demonstrated its potential as a natural Nrf2 activator and an effective agent for mitigating DN. Its multifaceted approach to addressing the key drivers of DN, such as oxidative stress and renal fibrosis, provides a novel perspective on the treatment of this debilitating condition. The unique ability of tiliroside to activate Nrf2 and simultaneously scavenge reactive oxygen species (ROS) showcases its potential as a comprehensive therapy for DN.
Future research should explore tiliroside’s efficacy in clinical settings and further elucidate the mechanisms underlying its beneficial effects. Tiliroside’s emergence as a potential therapeutic option for DN offers hope for improving the quality of life for individuals suffering from this severe diabetic complication.
reference link : https://www.sciencedirect.com/science/article/pii/S1756464623004425#s0135