Angiopoietin-Like Protein 2 Promotes the Progression of Diabetic Kidney Disease.

Context: Angiopoietin-like protein 2 (ANGPTL2) is a circulating, proinflammatory protein. Objective: To examine the role of ANGPTL2 in the pathogenesis of diabetic kidney disease (DKD), we studied the epigenetic regulation of angptl2 expression in patients with diabetes. Design, Setting, Participants, and Intervention: We determined the relationship between serum ANGPTL2 levels and the progression of DKD in cross-sectional (220 patients) and cohort (145 patients, 7-year follow-up) studies. Furthermore, we investigated the direct effect of ANGPTL2 on podocyte function. Main Outcomes: The main outcome was progression of DKD. Results: We found that the expression of angptl2 was decreased by the methylation of its promoter region. Multivariate logistic regression analyses revealed that the baseline level of serum ANGPTL2 was an independent risk factor for the progression of DKD during follow-up periods. In cultured podocytes, ANGPTL2 directly increased albumin permeability through the translocation of zonula occludens-1 from the membrane to the cytosol via activation of focal adhesion kinase. Conclusions: ANGPTL2 might be directly involved in podocyte dysfunction and independently associated with the progression of DKD stages.

Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis.

The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIß and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.

Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis.

Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, α-naphthoflavon (αNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis.

Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate-induced colitis in mice.

The aryl hydrocarbon receptor (AhR) recognizes numerous small xenobiotic and natural molecules, such as dioxin and natural chemicals, and is involved in the metabolism of these compounds. AhR also has a regulatory role in inflammatory responses. This study investigated whether the activation of the AhR pathway affects dextran sodium sulfate (DSS)-induced colitis, an ulcerative colitis-like model, in mice. DSS-induced colitis was ameliorated by pretreatment with a potent AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in mice. In addition, the mice pretreated with TCDD showed increased prostaglandin E2 (PGE2) production in the colon, and inhibition of PGE2 production by indomethacin abrogated the inhibitory effects of TCDD on DSS-induced colitis. Collectively, the activation of the AhR pathway by TCDD may ameliorate DSS-induced colitis, at least in part, through PGE2 production.