bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019–09–01
two papers selected by
Laia Caja Puigsubira, Uppsala University
  1. Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension.
  2. Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48-linked Nox4 polyubiquitination and degradation via the inhibition of Smurf1 expression.
  1. Int J Mol Sci. 2019 Aug 28. pii: E4217. [Epub ahead of print]20(17):
    Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension.
    Ying Kang, Lei Ding, Hangbing Dai, Fangzheng Wang, Hong Zhou, Qing Gao, Xiaoqing Xiong, Feng Zhang, Tianrun Song, Yan Yuan, Guoqing Zhu, Yebo Zhou.
      Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160-180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.
    Keywords:  NADPH oxidase; angiotensin II; intermedin; obesity-related hypertension; paraventricular nucleus; sympathoexcitation
    DOI:  https://doi.org/10.3390/ijms20174217
  2. Br J Pharmacol. 2019 Aug 29.
    Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48-linked Nox4 polyubiquitination and degradation via the inhibition of Smurf1 expression.
    Zhiquan Chen, Xiaohong Sun, Qiuhong Chen, Tian Lan, Kaipeng Huang, Haiming Xiao, Zeyuan Lin, Yan Yang, Peiqing Liu, Heqing Huang.
       BACKGROUND AND PURPOSE: Nox4 is the major NADPH isoform in the kidney and contributes to the pathogenesis of diabetic nephropathy (DN). However, the molecular mechanisms of increased Nox4 expression induced by hyperglycaemia remain to be elucidated. Here, the role of the Connexin32 (Cx32)-Nox4 signalling axis in DN and its related mechanisms were investigated.
    EXPERIMENTAL APPROACH: A diabetic mouse model was induced by low-dose streptozotocin (STZ) combined with a high-fat diet. The effects of Cx32 on Nox4 expression as well as on renal function and fibrosis in STZ-induced diabetic mice were investigated using adenovirus-overexpressing Cx32 and Cx32-deficient mice. The interaction between Cx32 and Nox4 was analysed by co-immunoprecipitation and immunofluorescence assays.
    KEY RESULTS: In this study, we identified that Cx32 was down-regulated in the kidneys of diabetic mice. Overexpression of Cx32 reduced the expression of Nox4 and improved renal function and fibrosis in STZ-induced diabetic mice, whereas Cx32 deficiency had opposite effects. The regulation of Cx32 in fibronectin (FN) expression was not completely dependent on gap junctional intercellular communication involving Cx32. Moreover, Cx32 interacted with Nox4 and reduced the generation of hydrogen peroxide, eventually down-regulating FN expression. Mechanistically, Cx32 decreased Nox4 expression by promoting its K48-linked polyubiquitination. Interestingly, Smurf1overexpression inhibited K48-linked polyubiquitination of Nox4. Furthermore, Cx32 interacted with Smurf1 and inhibited its expression.
    CONCLUSION AND IMPLICATIONS: Cx32 ameliorates renal fibrosis in diabetic mice by promoting K48-linked Nox4 polyubiquitination and degradation via the inhibition of Smurf1 expression. Targeting the Cx32-Nox4 signalling axis may contribute to the development of novel therapeutics for DN.
    Keywords:  Cx32; Nox4; Smurf1; diabetic nephropathy (DN); oxidative stress; polyubiquitination
    DOI:  https://doi.org/10.1111/bph.14853
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