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      Intermedin inhibits unilateral ureteral obstruction-induced oxidative stress via NADPH oxidase Nox4 and cAMP-dependent mechanisms

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          NADPH oxidase Nox4-derived reactive oxygen species (ROS) play important roles in renal fibrosis. Our previous study demonstrated that intermedin (IMD) alleviated unilateral ureteral obstruction (UUO)-induced renal fibrosis by inhibition of ROS. However, the precise mechanisms remain unclear. Herein, we investigated the effect of IMD on Nox4 expression and NADPH oxidase activity in rat UUO model, and explored if these effect were achieved through cAMP-PKA pathway, the important post-receptor signal transduction pathway of IMD, in TGF-β1-stimulated rat proximal tubular cell (NRK-52E). Renal fibrosis was induced by UUO. NRK-52E was exposed to rhTGF-β1 to establish an in vitro model of fibrosis. IMD was overexpressed in the kidney and in NRK-52E by IMD gene transfer. We studied UUO-induced ROS by measuring dihydroethidium levels and lipid peroxidation end-product 4-hydroxynonenal expression. Nox4 expression in the obstructed kidney of UUO rat or in TGF-β1-stimulated NRK-52E was measured by quantitative RT-PCR and Western blotting. We analyzed NADPH oxidase activity using a lucigenin-enhanced chemiluminescence system. We showed that UUO-stimulated ROS production was remarkably attenuated by IMD gene transfer. IMD overexpression inhibited UUO-induced up-regulation of Nox4 and activation of NADPH oxidase. Consistent with in vivo results, TGF-β1-stimulated increase in Nox4 expression and NADPH oxidase activity was blocked by IMD. In NRK-52E, these beneficial effects of IMD were abolished by pretreatment with N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89), a PKA inhibitor, and mimicked by a cell-permeable cAMP analog dibutyl-cAMP. Our results indicate that IMD exerts anti-oxidant effects by inhibition of Nox4, and the effect can be mediated by cAMP-PKA pathway.

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          Most cited references 15

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          Cellular and molecular mechanisms in kidney fibrosis.

          Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution.
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            Identification of renox, an NAD(P)H oxidase in kidney.

            Oxygen sensing is essential for homeostasis in all aerobic organisms, but its mechanism is poorly understood. Data suggest that a phagocytic-like NAD(P)H oxidase producing reactive oxygen species serves as a primary sensor for oxygen. We have characterized a source of superoxide anions in the kidney that we refer to as a renal NAD(P)H oxidase or Renox. Renox is homologous to gp91(phox) (91-kDa subunit of the phagocyte oxidase), the electron-transporting subunit of phagocytic NADPH oxidase, and contains all of the structural motifs considered essential for binding of heme, flavin, and nucleotide. In situ RNA hybridization revealed that renox is highly expressed at the site of erythropoietin production in the renal cortex, showing the greatest accumulation of renox mRNA in proximal convoluted tubule epithelial cells. NIH 3T3 fibroblasts overexpressing transfected Renox show increased production of superoxide and develop signs of cellular senescence. Our data suggest that Renox, as a renal source of reactive oxygen species, is a likely candidate for the oxygen sensor function regulating oxygen-dependent gene expression and may also have a role in the development of inflammatory processes in the kidney.
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              Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases.

              Progression of fibrosis involves interstitial hypercellularity, matrix accumulation, and atrophy of epithelial structures, resulting in loss of normal function and ultimately organ failure. There is common agreement that the fibroblast/myofibroblast is the cell type most responsible for interstitial matrix accumulation and consequent structural deformations associated with fibrosis. During wound healing and progressive fibrotic events, fibroblasts transform into myofibroblasts acquiring smooth muscle features, most notably the expression of alpha-smooth muscle actin and synthesis of mesenchymal cell-related matrix proteins. In renal disease, glomerular mesangial cells also acquire a myofibroblast phenotype and synthesize the same matrix proteins. The origin of interstitial myofibroblasts during fibrosis is a matter of debate, where the cells are proposed to derive from resident fibroblasts, pericytes, perivascular adventitial, epithelial, and/or endothelial sources. Regardless of the origin of the cells, transforming growth factor-beta1 (TGF-β1) is the principal growth factor responsible for myofibroblast differentiation to a profibrotic phenotype and exerts its effects via Smad signaling pathways involving mitogen-activated protein kinase and Akt/protein kinase B. Additionally, reactive oxygen species (ROS) have important roles in progression of fibrosis. ROS are derived from a variety of enzyme sources, of which the nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase family has been identified as a major source of superoxide and hydrogen peroxide generation in the cardiovasculature and kidney during health and disease. Recent evidence indicates that the NAD(P)H oxidase homolog Nox4 is most accountable for ROS-induced fibroblast and mesangial cell activation, where it has an essential role in TGF-β1 signaling of fibroblast activation and differentiation into a profibrotic myofibroblast phenotype and matrix production. Information on the role of ROS in mesangial cell and fibroblast signaling is incomplete, and further research on myofibroblast differentiation during fibrosis is warranted.

                Author and article information

                Ren Fail
                Ren Fail
                Renal Failure
                Taylor & Francis
                14 August 2017
                : 39
                : 1
                : 652-659
                [a ] Department of Nephrology, Second Hospital of Shanxi Medical University , Shanxi, China;
                [b ] Shanxi Kidney Disease Institute , Shanxi, China;
                [c ] Department of Microbiology and Immunology, Shanxi Medical University , Taiyuan, Shanxi, China
                Author notes

                These authors have contributed equally to this article and they are co-first authors.

                CONTACT Xi Qiao qiaoxi7347@ 123456126.com Department of Nephrology, Second Hospital of Shanxi Medical University, Shanxi Kidney Disease Institute , 382# WuYi Road, Taiyuan030001, PR China
                © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 8, Words: 3818
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81100531
                Funded by: Shanxi Province Health and Family Planning Commission, Science and Technology Project
                Award ID: 201601043
                Funded by: Shanxi Province Scientific Research Foundation
                Award ID: 2010-58
                This work was supported by the National Natural Science Foundation of China [Grant no. 81100531]; Shanxi Province Health and Family Planning Commission, Science and Technology Project [Grant no. 201601043]; and Shanxi Province Scientific Research Foundation for the Returned Overseas Chinese Scholars [Grant no. 2010-58].
                Laboratory Study


                intermedin, nadph oxidase, reactive oxygen species, camp, renal


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