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      Sorting Nexin 5 and Dopamine D1 Receptor Regulate the Expression of the Insulin Receptor in Human Renal Proximal Tubule Cells

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          Abstract

          Sorting nexin 5 (SNX5) belongs to the SNX family, which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins, receptors, and transporters. SNX5 is important in the resensitization of the dopamine D1-like receptor (D1R). D1R is uncoupled from its effector proteins in hypertension and diabetes, and treatment of diabetes restores D1R function and insulin receptor (IR) expression. We tested the hypothesis that the D1R and SNX5 regulate IR by studying the expression, distribution, dynamics, and functional consequences of their interaction in human renal proximal tubule cells (hRPTCs). D1R, SNX5, and IR were expressed and colocalized in the brush border of RPTs. Insulin promoted the colocalization of SNX5 and IR at the perinuclear area of hRPTCs. Unlike SNX5, the D1R colocalized and coimmunoprecipitated with IR, and this interaction was enhanced by insulin. To evaluate the role of SNX5 and D1R on IR signaling, we silenced via RNA interference the endogenous expression of SNX5 or the D1R gene DRD1 in hRPTCs. We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B, which are crucial components of the IR signal transduction pathway. Our data indicate that SNX5 and D1R are necessary for normal IR expression and activity. It is conceivable that D1R and SNX5 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling.

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          Most cited references 50

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          The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.

          The serine/threonine protein kinase encoded by the Akt proto-oncogene is catalytically inactive in serum-starved primary and immortalized fibroblasts. Here we show that Akt and the Akt-related kinase AKT2 are activated by PDGF. The activation was rapid and specific, and it was abrogated by mutations in the Akt Pleckstrin homology (PH) domain. The Akt activation was also shown to depend on PDGFR beta tyrosines Y740 and Y751, which bind phosphatidylinositol 3-kinase (PI 3-kinase) upon phosphorylation. Moreover, Akt activation was blocked by the PI 3-kinase-specific inhibitor wortmannin and the dominant inhibitory N17Ras. Conversely, Akt activity was induced following the addition of phosphatidylinositol-3-phosphate to Akt immunoprecipitates from serum-starved cells in vitro. These results identify Akt as a novel target of PI 3-kinase and suggest that the Akt PH domain may be a mediator of PI 3-kinase signaling.
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            The kidney, hypertension, and obesity.

             Daniel Hall (2003)
            This paper provides a personal perspective of the role of abnormal renal-pressure natriuresis in the pathogenesis of hypertension. Direct support for a major role of renal-pressure natriuresis in long-term control of arterial pressure and sodium balance comes from studies demonstrating that (1) pressure natriuresis is impaired in all forms of chronic hypertension and (2) prevention of pressure natriuresis from operating, by servo-control of renal perfusion pressure, also prevents the maintenance of sodium balance hypertension. Although the precise mechanisms of impaired pressure natriuresis in essential hypertension have remained elusive, recent evidence suggests that obesity and overweight may play a major role. Obesity increases renal sodium reabsorption and impairs pressure natriuresis by activation of the renin-angiotensin and sympathetic nervous systems and by altered intrarenal physical forces. Chronic obesity also causes marked structural changes in the kidneys that eventually lead to a loss of nephron function, further increases in arterial pressure, and severe renal injury in some cases. Although there are many unanswered questions about the mechanisms of obesity hypertension and renal disease, this is one of the most promising areas for future research, especially in view of the growing, worldwide "epidemic" of obesity.
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              Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.

               K D Copps,  M F White (2012)
              The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
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                Author and article information

                Journal
                Endocrinology
                The Endocrine Society
                0013-7227
                1945-7170
                June 01 2015
                June 01 2015
                November 14 2016
                : 156
                : 6
                : 2211-2221
                Affiliations
                [1 ]Department of Physiology and Biophysics (F.L., P.A.J.), Georgetown University Medical Center, Washington, DC 20057;
                [2 ]Liver Disease Branch (F.L.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892;
                [3 ]Department of Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing 400042, People's Republic of China;
                [4 ]Division of Nephrology (J.Y.J.E.J., V.A.M.V., P.Y., I.A., P.A.J.), Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201;
                [5 ]University of Virginia Health Sciences Center (R.A.F.), Charlottesville, Virginia 22908
                [6 ]Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, Maryland 21201;
                Article
                10.1210/en.2014-1638
                © 2016

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