Protective Effects of Kaempferitrin on Advanced Glycation End Products Induce Mesangial Cell Apoptosis and Oxidative Stress

Abstract

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) both play important roles in diabetic nephropathy (DN). Previous studies have identified glomerular mesangial cells (GMCs) injury as a key early risk factor in the development of DN. Kaempferitrin (KM) is a potent antioxidant with hypoglycemic action. Although KM is known to protect against AGE-induced damage in GMCs, the effects and the mechanisms by which they occur are poorly understood. In this study, cultured rat GMCs were exposed to AGE-induced oxidative stress (OS) to model DN in vitro. Reactive oxygen species (ROS) was analyzed by 2′,7′-dichlorofluorescin diacetate (DCFH-DA). Superoxide dismutase (SOD) and malondialdehyde (MDA) were studied using commercial kits. Mitochondrial membrane potential (Δψm) was measured by rhodamine 123. Hoechst 33258 and annexin V and propidium iodide (PI) double staining were performed to observe the apoptosis states in GMCs, whereas apoptosis and protective mechanism in AGE-induced GMCs were investigated by Western blot. The data revealed that KM effectively increased SOD activity, decreased MDA levels, suppressed ROS generation, and protected against OS in AGE-induced GMCs. Treatment with KM also inhibited the expression of collagen IV and transforming growth factor-β1 (TGF-β1), improved mitochondrial membrane potential recovery, and suppressed the mitochondrial/cytochrome c-mediated apoptosis pathway through the expression of anti-apoptotic factors in GMCs in vitro. These findings suggest that KM may be a new potential agent in the treatment of DN in future.

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

“…Hou et al demonstrated that Salvianolic acid A prevented from diabetic nephropathy by restraining AGE-RAGE-NOX4 with validated safety for the first time [19], which dramatically accelerated the advances of drug discovery since myriad compounds concerning AGE-RAGE inhibition and diabetic nephropathy regression had been withdrawn from clinical trials due to its unsatisfactory safety [130]. Resveratrol [131,132], kaempferitrin [133] and chrysin [134] could reduce renal damage through AGE/RAGE or Nrf2-Keap1 in animal models of diabetic nephropathy. Additionally, resveratrol also played paramount roles in protecting against diabetic renal fibrosis [135], aging kidney [66] and kidney damage [136,137] in animal models.…”

The Coming Age of Flavonoids in the Treatment of Diabetic Complications

“…In this study, kaempferitrin reduced AGE-induced oxidative stress by increasing SOD activity and by reducing MDA levels and ROS generation. Moreover, this flavonoid prevented the increase in collagen IV and TGF-β1 levels [75]. The anti-fibrotic effect has also been demonstrated by other flavonoids such as chrysin which inhibited AGEs-induced expression of collagens, and matrix metalloproteinases in mesangial cells and prevented collagen and AGEs accumulation in diabetic kidneys from the db/db mouse model of T2D [77].…”

“…The flavanone naringin also attenuates ROS production in diabetic kidneys with concomitant reduction in Nox4 expression and increase in antioxidant enzymes SOD and GPx [74]. In vitro experiments have also demonstrated that the strong anti-oxidant effect of different flavonoids (e.g., corn silk extracts and liquiritigenin) is linked to Nox4 inhibition and SOD induction [68,69,75].…”

“…Therefore, the blockade of AGEs and their receptor system (RAGEs) as well as downstream related pathways has become another therapeutic target for the treatment of DN [76]. In this regard, the protective effect of kaempferitrin was evaluated in glomerular mesangial cells exposed to AGEs [75]. In this study, kaempferitrin reduced AGE-induced oxidative stress by increasing SOD activity and by reducing MDA levels and ROS generation.…”

Determination of (+)-Dihydrorobinetin as An Active Constituent of the Radical-Scavenging Activity of Asana (Pterocarpus marsupium) Heartwood

“…AGEs are known to induce melanogenesis as well as generate reactive oxygen species by binding to AGE receptors. 11,12 The DPPH radical-scavenging activity and suppressive activity on AGEs production of DHR suggest that the improvement in diabetes achieved by consuming a decoction of Asana is partly attributable to DHR.…”