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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Wang, Renjun, et al.
(författare)
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Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus
- 2016
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic heart failure (CHF) increases sympathoexcitation through angiotensin II (ANG II) receptors (AT1R) in the paraventricular nucleus (PVN). Recent publications indicate both γ-aminobutyric acid B-type receptor 1 (GABBR1) and microRNA-7b (miR-7b) are expressed in the PVN. We hypothesized that ANG II regulates sympathoexcitation through homeobox D10 (HoxD10), which regulates miR-7b in other tissues.METHODS AND RESULTS: Ligation of the left anterior descendent coronary artery in rats caused CHF and sympathoexcitation. PVN expression of AT1R, HoxD10, and miR-7b was increased, whereas GABBR1 was lower in CHF. Infusion of miR-7b in the PVN caused sympathoexcitation in control animals and enhanced the changes in CHF. Antisense miR-7b infused in PVN normalized GABBR1 expression while attenuating CHF symptoms, including sympathoexcitation. A luciferase reporter assay detected miR-7b binding to the 3' untranslated region of GABBR1 that was absent after targeted mutagenesis. ANG II induced HoxD10 and miR-7b in NG108 cells, effects blocked by AT1R blocker losartan and by HoxD10 silencing. miR-7b transfection into NG108 cells decreased GABBR1 expression, which was inhibited by miR-7b antisense. In vivo PVN knockdown of AT1R attenuated the symptoms of CHF, whereas HoxD10 overexpression exaggerated them. Finally, in vivo PVN ANG II infusion caused dose-dependent sympathoexcitation that was abrogated by miR-7b antisense and exaggerated by GABBR1 silencing.CONCLUSIONS: There is an ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway in the PVN that contributes to sympathoexcitation and deterioration of cardiac function in CHF.
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| 3. |
- Yang, Ting, et al.
(författare)
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Abrogation of adenosine A(1) receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 58:7, s. 1610-1620
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Adenosine is an important regulator of metabolism; however, the role of the A(1) receptor during ageing and obesity is unclear. The aim of this study was to investigate the effects of A(1) signalling in modulating metabolic function during ageing. Methods Age-matched young and aged A (1) (also known as Adora1)-knockout (A (1) (-/-)) and wild-type (A (1) (+/+)) mice were used. Metabolic regulation was evaluated by body composition, and glucose and insulin tolerance tests. Isolated islets and islet arterioles were used to detect islet endocrine and vascular function. Oxidative stress and inflammation status were measured in metabolic organs and systemically. Results Advanced age was associated with both reduced glucose clearance and insulin sensitivity, as well as increased visceral adipose tissue (VAT) in A (1) (+/+) compared with A (1) (-/-) mice. Islet morphology and insulin content were similar between genotypes, but relative changes in in vitro insulin release following glucose stimulation were reduced in aged A (1) (+/+) compared with A (1) (-/-) mice. Islet arteriolar responses to angiotensin II were stronger in aged A (1) (+/+) mice, this being associated with increased NADPH oxidase activity. Ageing resulted in multiple changes in A (1) (+/+) compared with A (1) (-/-) mice, including enhanced NADPH oxidase-derived O-2 (-) formation and NADPH oxidase isoform 2 (Nox2) protein expression in pancreas and VAT; elevated levels of circulating insulin, leptin and proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-12); and accumulation of CD4(+) T cells in VAT. This was associated with impaired insulin signalling in VAT from aged A (1) (+/+) mice. Conclusions/interpretation These studies emphasise that A(1) receptors regulate metabolism and islet endocrine and vascular functions during ageing, including via the modulation of oxidative stress and inflammatory responses, among other things.
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| 4. |
- Zhang, Suping, et al.
(författare)
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Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition
- 2018
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-beta 1 (TGF beta 1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of alpha-smooth muscle actin (alpha-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT-related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGF beta 1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF-kappa B) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT.
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| 5. |
- Zhou, Suhan, et al.
(författare)
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ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function
- 2019
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 316:1, s. F134-F145
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Tidskriftsartikel (refereegranskat)abstract
- 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 Set(473) and eNOS at Ser(1177). 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. rhADAMIS13 could be a promising strategy to treat AKI in clinical settings.
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