Fucoxanthin Improves Diabetic Nephropathy Fibrosis Through Alleviating Oxidative Stress

Diabetic nephropathy(DN)is a serious diabetic microvascular complication,which is one of the main causes of end-stage renal failure.Among the complicated pathogenesis of DN,oxidative stress is the main cause to aggravate the process of DN.Fucoxanthin(FX)is a natural marine-derived carotenoid with strong anti-oxidation activity.In the previous study,it was found that FX has a promising anti-DN activity.In the present study,we aimed to explore the specific mechanisms of the anti-DN activity of FX.We firstly explored the role of forkhead box O family 3 alpha(Fox O3α)in the protective effect of FX on DN.Previous studies show Fox O3α-mediated anti-oxidative stress plays an important role in DN.The transcriptional activity of Fox O3α is regulated by serine/threonine phosphatase(Akt)and silent information regulator T1(Sirt1),that the phosphorylation and acetylation of Fox O3α accelerate the ubiquitination and degradation of Fox O3α and reduce its transcriptional activity.Here we aimed to explore whether FX could alleviate oxidative stress in DN by activating Fox O3α and its specific mechanism.We found that in high glucose cultured glomerular mesangial cells(GMCs),FX treatment significantly reduced the expression of superoxide species(ROS),fibronectin(FN)and collagen IV,suggesting that FX can reduce oxidative stress and the accumulation of mesangial matrix.What’s more,Akt inhibitor MK2206 treatment decreased the phosphorylation level of Fox O3α,while resveratrol(RSV)administration decreased the acetylation level of Fox O3α.Interestingly,FX decreased both phosphorylation and acetylation level of Fox O3α,which reversed the inhibition of high glucose on the expression of Fox O3α and promoted the nuclear transportation of Fox O3α.Furthermore,the combined administration of Akt activator SC79 or Sirt1 inhibitor EX527 and FX reduced the activation effect of FX on Fox O3α.FX also promoted the expression of manganese superoxide dismutase(Mn SOD),the downstream target of Fox O3α,which was also weakened by SC79 or EX527 administration.These results showed that FX reduced the oxidative stress in high glucose-induced GMCs,further alleviated fibrosis of GMCs through Akt/Sirt1/Fox O3α signaling.We next explored the role of nuclear factor 2-related factor 2(Nrf2),a transcription factor of an antioxidant element,in the protective effect of FX on DN.Sirt1,as a deacetylase,has an important role in delay aging through mediating oxidative stress.We further explored whether FX could reduce oxidative stress and alleviate the DN process through Nrf2 signaling,and whether Sirt1 was involved in this process.The results showed that the expression of Sirt1 and Nrf2 decreased in the kidney of diabetic rats and GMCs cultured in high glucose,however,FX effectively upregulated the lower expression of Sirt1 and Nrf2.Furthermore,Sirt1 activator RSV increased Sirt1 and Nrf2 expression,while Sirt1 inhibitor EX527 decreased the activation effect of FX on Sirt1 and Nrf2.In vivo and in vitro experiments,we found FX treatment reversed the inhibition of Cu/Zn superoxide dismutase(SOD)and heme oxidase 1(HO-1),and reduced the overexpression of FN and collagen IV.In addition,FX treatment effectively improved the renal metabolism parameters of diabetic rats and reduced fibrosis damage.These results suggest that FX has a good therapeutic effect on DN,and its mechanism is partially through Sirt1/Nrf2 signaling to reduce the level of oxidative stress.Based on the above results,we conclude that FX could effectively reduce the fibrosis process of DN in vivo and in vitro by reducing oxidative stress,which is dependent on the regulation of Akt/Sirt1/Fox O3α signaling and Sirt1/Nrf2 signaling.