Flavonoids on diabetic nephropathy: advances and therapeutic opportunities

Abstract

With the advances in biomedical technologies, natural products have attracted substantial public attention in the area of drug discovery. Flavonoids are a class of active natural products with a wide range of pharmacological effects that are used for the treatment of several diseases, in particular chronic metabolic diseases. Diabetic nephropathy is a complication of diabetes with a particularly complicated pathological mechanism that affects at least 30% of diabetic patients and represents a great burden on public health. A large number of studies have shown that flavonoids can alleviate diabetic nephropathy. This review systematically summarizes the use of common flavonoids for the treatment of diabetic nephropathy. We found that flavonoids play a therapeutic role in diabetic nephropathy mainly by regulating oxidative stress and inflammation. Nrf-2/GSH, ROS production, HO-1, TGF-β1 and AGEs/RAGE are involved in the process of oxidative stress regulation. Quercetin, apigenin, baicalin, luteolin, hesperidin, genistein, proanthocyanidin and eriodictyol were found to be capable of alleviating oxidative stress related to the aforementioned factors. Regarding inflammatory responses, IL-1, IL-6β, TNF-α, SIRT1, NF-κB, and TGF-β1/smad are thought to be essential. Quercetin, kaempferol, myricetin, rutin, genistein, proanthocyanidin and eriodictyol were confirmed to influence the above targets. As a result, flavonoids promote podocyte autophagy and inhibit the overactivity of RAAS by suppressing the upstream oxidative stress and inflammatory pathways, ultimately alleviating DN. The above results indicate that flavonoids are promising drugs for the treatment of diabetic nephropathy. However, due to deficiencies in the effect of flavonoids on metabolic processes and their lack of structural stability in the body, further research is required to address these issues.

Nephroprotective Effects of Synthetic Flavonoid Hidrosmin in Experimental Diabetic Nephropathy

“…Despite the enormous advances on cardiovascular and renal protection provided by the SGLT2i and GLP-1 RA introduced in clinical practice for diabetic patients [ 15 , 16 , 17 ], no drug targeting inflammation and redox balance signaling pathways, key elements in the genesis and progression of DN [ 7 , 18 ], is available so far. Flavonoid compounds seem to be a promising alternative to treat chronic DM complications due to their outstanding pharmacological effects including anti-inflammatory, antioxidant, antidiabetic, and antihypertensive, as evinced in experimental models and clinical studies [ 20 , 33 , 34 ]. The synthetic flavonoid hidrosmin, a diosmin-derived flavone with vasoprotective effects [ 35 ], is a venotonic agent used for many years in patients suffering from chronic venous insufficiency mainly due to its antiedematous properties and other beneficial effects (i.e., in swelling and leg cramps), more effective in some cases than diosmin [ 21 , 36 ]; however, the therapeutic effects of hidrosmin in other chronic diseases remains to be explored.…”

Unraveling the Mechanism of Zhibaidihuang Decoction against IgA Nephropathy Using Network Pharmacology and Molecular Docking Analyses

“…anticancer mechanisms (Hosseini et al 2021). Quercetin is known to relieve diabetic nephropathy by inhibiting inflammatory and oxidative stress inflammatory pathways (Hu et al 2021). Meanwhile, some studies have also demonstrated that quercetin exerted a nephroprotective effect by regulating macrophage polarization (Lu et al 2018).…”

“…Meanwhile, some studies have also demonstrated that quercetin exerted a nephroprotective effect by regulating macrophage polarization (Lu et al 2018). Kaempferol as well has been demonstrated to have a nephroprotective effect through its anti-inflammatory and antioxidant action (Hu et al 2021).…”

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

“…It possesses many biological roles, while in DKD, it shows an anti-fibrotic and antioxidant effect, the last one in an NRF2 partially dependent pathway [ 165 , 166 ]. Other representatives that can trigger the NRF2/KEAP1/ARE pathway are Diphlorethohydroxycarmalol, derived from Ishige okamurae, a species of algae [ 167 ], Genistein [ 6 ], Hesperetin [ 168 ], Myricetin [ 169 ] and Digitoflavone (3,0,4,5,7-tetrahydroxyflavone) [ 170 , 171 ]. Further, some potential NRF2 activators that are part of the same family have been studied in DKD, with promising results, such as Auricularia cornea [ 172 ].…”