Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway.

Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor ß (TGFß)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.

Treatment of aortic root aneurysm and mitral valve pathology through a single aortotomy.

BACKGROUND: Aortic root aneurysms combined with lesions of the mitral valve requires synchronous operations. The conventional approach is to treat the two lesions through separate aortic and atrial incisions. METHODS: From May 2009 to August 2012, 28 transaortic mitral valve operations were performed. There were 23 males and five females, the age ranged from 18 to 75 years, mean 41 ± 16 years. The operative procedures included Bentall+MVR in 20 patients, Bentall+MVP in three patients, Bentall+total arch replacement+stent elephant trunk+MVP in one patient, Bentall+total arch replacement+stent elephant trunk+MVR in two patients, Bentall+MVP+CABG in two patients. Follow-up was completed for all patients, with a mean follow-up period of 22 ± 10 months and a maximum of 42 months. RESULTS: Transaortic mitral valve surgery was successful for all patients. There was a reoperation in two patients for bleeding. In the MVP group, there was mild regurgitation in two cases before discharge, without further development during the follow-up. In the MVR group, there was paravalvular leakage in one patient three months later, which required repair. There were no deaths in the hospital and the follow-up period, and no valve-associated complication during the follow-up period. The heart function of all patients during the follow-up period was Level I-II (NYHA). CONCLUSION: Transaortic mitral valve operation is a feasible surgical approach to treat patients with aortic root aneurysms combined with mitral valve lesions.