Hangyu Tian,Dan Yu,Yan Hu,Pan Zhang,Yang Yang,Qiang Hu,Ming Li
Angiotensin II (Ang II) is a principal molecule of the renin‑angiotensin system, which promotes hypertrophy and fibrosis. It has been demonstrated that Ang II upregulates the expression of cyclophilin A (CypA), which is a potential myocardial hypertrophy factor. However, the mechanisms by which Ang II induces the expression of CypA in cardiomyocytes remain unclear. In the present study, reactive oxygen species (ROS) were detected by fluorescence microscopy, and western blot analysis and ELISA were used to measure CypA expression. It was identified that Ang II enhanced the production of ROS in rat cardiomyocytes. ROS, in turn, promoted CypA expression and secretion. Notably, the action of Ang II was primarily dependent on the angiotensin type 2 receptor (AT2R), not the type 1 receptor. These results provided an insight into the role of the AT2R signaling pathway in Ang II‑induced myocardial hypertrophy.
Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT 1 R) and type 2 receptor (AT 2 R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT 2 (pAT 2 ) to form iRGD-PEI-MWNT-SS-CD/pAT 2 complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and AT 1 R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT 2 and efficiently inhibited angiogenesis . iRGD-PEI-MWNT-SS-CD/pAT 2 complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice . Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy.
Diabetic nephropathy (DN) is the most prevalent microvascular complication of diabetes, where a hyperglycemic environment can induce chronic damage to renal vessels and parenchyma, severely endangering patients’ health. TangShenKang decoction (TSK) is a traditional Chinese medicine formula developed based on the clinical and pathological characteristics of DN. In this study, through transcriptomic data analysis of a rat DN model and a TSK intervention group, the key regulatory gene AT2R was identified. Molecular mechanisms underlying TSK’s effects on inflammation and fibrosis in DN were investigated using Western blot, quantitative polymerase chain reaction (qPCR), and immunofluorescence staining experiments, with further in vivo validation of TSK’s therapeutic effects on DN. The results showed that TSK can activate AT2R in the DN model and promote SHP1 phosphorylation, thereby inhibiting the phosphorylation of IκBα, an important protein in the NFκB signaling pathway, reducing the secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and suppressing the progression of inflammation. Meanwhile, after activating AT2R, TSK can effectively inhibit the epithelial-mesenchymal transition (EMT) process in DN, downregulate the expression of p-Smad2/3 in the TGF-β signaling axis, and decrease the expression levels of fibrosis phenotype molecules such as connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and fibronectin 1 (FN1), thereby alleviating renal fibrosis in DN. In conclusion, the therapeutic effect of TSK on DN may be mediated through the activation of the AT2R/ATIP1/SHP1 axis, which subsequently inhibits inflammation- and fibrosis-related signaling pathways.
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