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      Albumin Activation of NAD(P)H Oxidase Activity Is Mediated via Rac1 in Proximal Tubule Cells

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          Background: Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. Methods: To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. Results: We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 µg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 µ M, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. Conclusions: These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.

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          Most cited references 20

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          Regulation of NADPH oxidases: the role of Rac proteins.

           Peter Hordijk (2006)
          The role for reactive oxygen species (ROS) in cellular (patho)physiology, in particular in signal transduction, is increasingly recognized. The family of NADPH oxidases (NOXes) plays an important role in the production of ROS in response to receptor agonists such as growth factors or inflammatory cytokines that signal through the Rho-like small GTPases Rac1 or Rac2. The phagocyte oxidase (gp91phox/NOX2) is the best characterized family member, and its mode of activation is relatively well understood. Recent work has uncovered novel and increasingly complex modes of control of the NOX2-related proteins. Some of these, including NOX2, have been implicated in various aspects of (cardio)vascular disease, including vascular smooth muscle and endothelial cell hypertrophy and proliferation, inflammation, and atherosclerosis. This review focuses on the role of the Rac1 and Rac2 GTPases in the activation of the various NOX family members.
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            Regulation of receptor-mediated endocytosis by Rho and Rac.

            Pinocytosis and membrane ruffling are among the earliest and most dramatic cellular responses to stimulation by growth factors or other mitogens. The small Ras-related G proteins Rho and Rac have a regulatory role in membrane ruffling and activated Rho has been shown to stimulate pinocytosis when microinjected into Xenopus oocytes. In contrast to these well established effects of Rho and Rac on plasma membrane morphology and bulk pinocytosis, there has been no evidence for their involvement in the regulation of receptor-mediated endocytosis in clathrin-coated pits. Here we show that activated Rho and Rac inhibit transferrin-receptor-mediated endocytosis when expressed in intact cells. Furthermore, we have reconstituted these effects in a cell-free system and established that Rho and Rac can regulate clathrin-coated vesicle formation.
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              Role of gp91phox (Nox2)-containing NAD(P)H oxidase in angiogenesis in response to hindlimb ischemia.

              Neovascularization is potentially important for the treatment of ischemic heart and limb disease. We reported that reactive oxygen species (ROS) derived from gp91phox (Nox2)-containing NAD(P)H oxidase are involved in angiogenesis in mouse sponge models as well as in vascular endothelial growth factor (VEGF) signaling in cultured endothelial cells. The role of gp91phox-derived ROS in neovascularization in response to tissue ischemia is unknown, however. Here, we show that neovascularization in the ischemic hindlimb is significantly impaired in gp91phox-/- mice as compared with wild-type (WT) mice as evaluated by laser Doppler flow, capillary density, and microsphere measurements. In WT mice, inflammatory cell infiltration in the ischemic hindlimb was maximal at 3 days, whereas capillary formation was prominent at 7 days when inflammatory cells were no longer detectable. Increased O2*- production and gp91phox expression were present at both time points. The dihydroethidium staining of ischemic tissues indicates that O2*- is mainly produced from inflammatory cells at 3 days and from neovasculature at 7 days after operation. Relative to WT mice, ischemia-induced ROS production in gp91phox-/- mice at both 3 and 7 days was diminished, whereas VEGF expression was enhanced and the inflammatory response was unchanged. Infusion of the antioxidant ebselen into WT mice also significantly blocked the increase in blood flow recovery and capillary density after ischemia. gp91phox-derived ROS play an important role in mediating neovascularization in response to tissue ischemia. NAD(P)H oxidases and their products are potential therapeutic targets for regulating angiogenesis in vivo.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                March 2007
                05 January 2007
                : 27
                : 1
                : 15-23
                aDepartment of Internal Medicine, bDivision of Nephrology, University of Missouri School of Medicine, cDepartment of Internal Medicine, Harry S. Truman VA Medical Center, Columbia, Mo., dUniversity of Arizona Diabetes Center and eVA Medical Center, Tucson, Ariz., USA
                98432 Am J Nephrol 2007;27:15–23
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 32, Pages: 9
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                Original Report: Laboratory Investigation


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