No abstract

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

BackgroundLeft ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited.Methods and ResultsWe created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)–23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M1 macrophages and neutrophils were the major cellular source of IL-23, whereas >90% of IL-17A-producing T cells in infarcted heart were CD4− TCRγδ+ (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression.ConclusionsThe IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.

A n acute aortic dissection (AAD) is initiated by an intimal tear, with resultant propagation within the middle third of the medial layer of the aorta. 1 To delineate treatment, the Stanford classification divides AAD into 2 types, type A and type B. Type A affects the ascending aorta, whereas type B does not. Type A AAD is more severe because of the higher mortality rate of 20% by 24 hours, 30% by 48 hours, 40% at 1 week, and 50% at 1 month.2 Thus, surgical repair is the first choice of treatment for patients with type A AAD to prevent life-threatening complications, including aortic rupture and cardiac tamponade. Although type B AAD is generally more benign and medical treatment for high blood pressure and intolerant pain can improve the patient's clinical outcome, a substantial proportion of medically treated patients still encounter catastrophic events within 7 days, such as aortic expansion and subsequent aortic rupture, visceral ischemia, and lung oxygenation impairment.2,3 Thoracic endovascular repair with stent grafting is the emerging therapeutic strategy Methods and Results: