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Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays an important role in the pathogenesis of hypertension and renal fibrosis. Toll-like receptor 4 (TLR4) signaling contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo-induced hypertension and renal damage is not clear. In the current study, rats were treated with Aldo-salt combined with TAK-242 (a TLR4 signaling antagonist) for 4 weeks. Hemodynamic, cardiac and renal parameters were assayed at the indicated time. We found that Aldo-salt–treated rats present cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of TLR4 as well as levels of molecular markers attesting inflammation and fibrosis are increased by Aldo infusion, whereas the treatment of TAK-242 reverses these alterations. TAK-242 suppresses cardiac and renal inflammatory cytokines levels (TNF-a, IL-1β and MCP-1). Furthermore, TAK-242 inhibits hypertension, cardiac and renal fibrosis, and also attenuates the Aldo-induced Epithelial-Mesenchymal Transition (EMT). In experimental hyperaldosteronism, upregulation of TLR4 is correlated with cardiac and renal fibrosis and dysfunction, and a TLR4 signaling antagonist, TAK-242, can reverse these alterations. TAK-242 may be a therapeutic option for salt-sensitive hypertension and renal fibrosis.

BackgroundSubstantial evidence suggests that high glucose (HG) causes endothelial cell damage; however, the potential mechanism therein has yet to be clarified. The aim of this study was to investigate the influence of HG on the endothelial-to-mesenchymal transition (EndMT) and its relevance to the activation of the renin-angiotensin system.MethodsPrimary human aortic endothelial cells (HAECs) were divided into three groups: a normal glucose (NG) group, HG group, and irbesartan (1 μM)-treated (HG+irbesartan) group. The concentration of angiotensin II in the supernatant was detected by radioimmunoassay. Pathological changes were investigated using fluorescence microscopy and electron microscopy. Immunofluorescence staining was performed to detect the co-expression of CD31 and fibroblast markers, such as fibroblast-specific protein 1 (FSP1). The expressions of FSP1 and α-SMA were detected by RT-PCR and Western blot.ResultsThe treatment of HAECs in the HG group resulted in significant increases in the expressions of FSP1 and angiotensin II in dose-and time-dependent manners. The incubation of HAECs exposure to HG resulted in a fibroblast-like phenotype, wherein increased microfilamentation and a roughened endoplasmic reticulum structure were observed in the cytoplasm. The expressions of FSP1 and α-SMA were significantly increased in the HG group, and these changes were inhibited by irbesartan treatment (P < 0.05). Double staining of the HAECs indicated a co-localization of CD31 and FSP1 and that some cells acquired spindle-shaped morphologies and a loss of CD31 staining; however, treatment with irbesartan attenuated the expression of EndMT (P < 0.05).ConclusionsThese findings suggest a novel mechanism in HG-induced endothelial damage via the mediation of the EndMT by angiotensin II, which was inhibited by Irbesartan.

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Emerging evidence has suggested that podocytes undergo epithelial-mesenchymal transition (EMT) in diabetic nephropathy (DN). Connective tissue growth factor (CTGF) and integrin-linked kinase (ILK) are involved in the progression of DN. However, the underlying mechanisms of EMT are not well understood. The study aimed to investigate the roles of CTGF and ILK in high glucose-induced phenotypic alterations of podocytes and determine whether ILK signaling is downstream of CTGF. The epithelial marker of nephrin and the mesenchymal marker of desmin were investigated by real-time RT-PCR and Western blotting. The results demonstrated that podocytes displayed a spreading, arborized morphology in normal glucose, whereas they had a cobblestone morphology in high glucose conditions, accompanied by decreased nephrin expression and increased desmin expression, suggesting podocytes underwent EMT. In response to high glucose, CTGF and ILK expression in podocytes were increased in a dose- and time-dependent manner, whereas the increase did not occur in the osmotic control. Furthermore, the inhibition of CTGF with anti-CTGF antibody prevented the phenotypic transition, as demonstrated by the preservation of epithelial morphology, the suppression of high glucose-induced desmin overexpression and the restoration of nephrin. Of note, the upregulation of ILK induced by high glucose was partially blocked by the inhibition of CTGF. In summary, these findings suggested that CTGF and ILK were involved in high glucose-induced phenotypic alterations of podocytes. ILK acted as a downstream kinase of CTGF and high glucose-induced ILK expression might occur through CTGF-dependent and -independent pathways.