Fenofibrate, a peroxisome proliferator-activated receptors α (PPARα) agonist, reduces vascular complications of diabetic patients but its protective mechanisms are not fully understood. Here we tested the hypothesis that fenofibrate improves vascular endothelial dysfunction by balancing endothelium-dependent relaxation and contractility of the aorta in diabetes mellitus (DM). In streptozotocin-induced diabetic mice, eight weeks of fenofibrate treatment (100 mg/Kg/d) improved endothelium dependent relaxation in the macro- and microvessels, increased nitric oxide (NO) levels, reduced renal damage markers and effects of the vasoconstrictor prostaglandin. Levels of superoxide dismutase and catalase were both reduced and hydrogen peroxide was increased in vehicle-treated DM, but these changes were reversed by fenofibrate treatment. Vasodilation of the aorta after fenofibrate treatment was reversed by PPARα or AMPKα inhibitors. Western blots showed that fenofibrate treatment elevated PPARα expression, induced liver kinase B1 (LKB1) translocation from the nucleus to the cytoplasm and activated AMP-activated protein kinase-α (AMPKα), thus activating endothelial NO synthase (eNOS). Also, fenofibrate treatment decreased NF-κB p65 and cyclooxygenase 2 proteins in aortas. Finally, incubation with indomethacin in vitro improved aortic contractility in diabetic mice. Overall, our results show that fenofibrate treatment in diabetic mice normalizes endothelial function by balancing vascular reactivity via increasing NO production and suppressing the vasoconstrictor prostaglandin, suggesting mechanism of action of fenofibrate in mediating diabetic vascular complications.

Background/Aims: Arterial fibrotic intimal thickening and arteriolar hyaline are considered common pathological features in immunoglobulin A nephropathy (IgAN), whereas little is known about the acute pathological manifestations of endothelial cell injury. The aim of this study was to investigate characteristics of intrarenal arterial lesions and to estimate their prognostic values in patients with IgAN. The primary renal endpoint was a 50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Methods: Various renal arterial lesions (arterial fibrotic intimal thickening, arteriolar hyaline, arteriolar endotheliocyte swelling, arteriolar inflammatory cell infiltration, and arteriolar thrombosis) in 1683 patients with IgAN were reviewed and reclassified using a semi-quantitative scoring system. Their correlations with clinical features, pathological characteristics, and renal outcomes were evaluated. Results: The prevalence of intrarenal arterial lesions was up to 72.2% in IgAN patients. There were 978 patients (58.1%) with arterial fibrotic intimal thickening, 350 patients (20.8%) with arteriolar hyaline, 432 patients (25.7%) with arteriolar endotheliocyte swelling, 356 patients (21.2%) with arteriolar inflammatory cell infiltration and 43 patients (2.6%) with arteriolar thrombosis. Arterial fibrotic intimal thickening and arteriolar hyaline were strongly associated with higher mean arterial pressure (MAP) and reduced eGFR (P < 0.001) but were not related to proteinuria at the time of renal biopsy. In contrast, arteriolar endotheliocyte swelling and arteriolar thrombosis were correlated with heavier proteinuria as well as higher MAP and reduced eGFR. During follow-up, patients with vascular lesions received more renin-angiotensin system (RAS) blockade and less glucocorticoid and showed poorer renal outcomes. Univariate Cox model showed that the presence of renal vascular lesions [hazard ratio (HR) = 25.01, 95% confidence interval (CI): 6.19 to 101.03, P < 0.001] was a risk factor for renal outcomes. However, in multivariable Cox analysis, which included clinical factors and the Oxford-MEST-C, vascular lesions were not significantly associated with an increased risk of renal failure. Remarkably, the impact of vascular lesions on the survival from ESRD or 50% reduction in renal function was eliminated by the use of RAS blockade after adjustment for eGFR, proteinuria, and MAP. Conclusion: Our study demonstrates the high prevalence of vascular lesions, including the chronic and acute arterial pathological changes, in patients with IgAN. The presence of vascular lesions is associated with higher MAP, reduced eGFR and poorer renal outcomes, which could be influenced by the RAS blockade treatment.

Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Ser473 and eNOS at Ser1177. Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis, and improving microvascular endothelial dysfunction. rhADAMTS13 could be a promising strategy to treat AKI in clinical settings.

Background/Aims: Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3β (GSK3β) pathways as well as the coordinating apoptosis and inflammation related proteins. Methods: The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3β pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice. Results: The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O₂^.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3β, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole. Conclusion: Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3β pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity.