title: Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells.
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.
authors.affiliation: Department of Physiology and Biophysics (F.L., P.A.J.), Georgetown University Medical Center, Washington, DC 20057; Liver Disease Branch (F.L.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Department of Nutrition (J.Y.), Daping Hospital, The Third Military Medical University, Chongqing 400042, People's Republic of China; Division of Nephrology (J.Y.J.E.J., V.A.M.V., P.Y., I.A., P.A.J.), Department of Medicine, and Department of Physiology (P.A.J.), University of Maryland School of Medicine, Baltimore, Maryland 21201; and University of Virginia Health Sciences Center (R.A.F.), Charlottesville, Virginia 22908.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: John Edward
authors.initials: JE
authors.lastname: Jones
authors.forename: Van Anthony M
authors.initials: VA
authors.lastname: Villar
authors.forename: Peiying
authors.initials: P
authors.lastname: Yu
authors.forename: Ines
authors.initials: I
authors.lastname: Armando
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D047468:Immunoprecipitation; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D058305:Sorting Nexins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017447:Receptors, Dopamine D1; C402667:SNX5 protein, human; D058305:Sorting Nexins; D011972:Receptor, Insulin
references.citation: Hypertension. 1996 Apr;27(4):955-61
references.pmid: 8613274
references.citation: J Biol Chem. 2010 Feb 19;285(8):5204-11
references.pmid: 20018868
references.citation: Clin Exp Hypertens. 2002 Apr;24(3):207-19
references.pmid: 11883792
references.citation: J Clin Invest. 1987 Apr;79(4):1104-9
references.pmid: 3549779
references.citation: Gen Pharmacol. 1995 Jul;26(4):727-35
references.pmid: 7635247
references.citation: MMWR Morb Mortal Wkly Rep. 2012 Sep 7;61:703-9
references.pmid: 22951452
references.citation: J Am Soc Nephrol. 2007 Oct;18(10):2661-71
references.pmid: 17855644
references.citation: Diabetologia. 2012 Oct;55(10):2565-82
references.pmid: 22869320
references.citation: Am J Physiol. 1995 Jan;268(1 Pt 2):R231-5
references.pmid: 7840326
references.citation: J Bioenerg Biomembr. 2012 Jun;44(3):351-5
references.pmid: 22528394
references.citation: J Biol Chem. 2012 Feb 24;287(9):6128-38
references.pmid: 22207758
references.citation: Clin Exp Hypertens. 2003 May;25(4):221-33
references.pmid: 12797596
references.citation: J Cell Biochem. 2010 Dec 15;111(6):1464-72
references.pmid: 20830743
references.citation: Curr Opin Nephrol Hypertens. 2012 Mar;21(2):171-8
references.pmid: 22274801
references.citation: J Clin Invest. 2008 Jun;118(6):2180-9
references.pmid: 18464932
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3872-7
references.pmid: 11904438
references.citation: Kidney Int. 2003 Dec;64(6):2163-71
references.pmid: 14633139
references.citation: Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1658-66
references.pmid: 18296567
references.citation: Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):797-801
references.pmid: 8290602
references.citation: Diabetes. 1999 Jul;48(7):1359-64
references.pmid: 10389839
references.citation: Cell. 1995 Jun 2;81(5):727-36
references.pmid: 7774014
references.citation: Am J Physiol Renal Physiol. 2013 Jan 1;304(1):F1-7
references.pmid: 23097467
references.citation: JAMA. 2010 May 26;303(20):2043-50
references.pmid: 20501926
references.citation: Mol Pharmacol. 2001 Feb;59(2):310-21
references.pmid: 11160868
references.citation: Biochem Biophys Res Commun. 2006 Apr 7;342(2):537-46
references.pmid: 16487940
references.citation: Science. 2001 Nov 30;294(5548):1939-42
references.pmid: 11729322
references.citation: Clin Exp Metastasis. 2000;18(8):683-93
references.pmid: 11827072
references.citation: J Biomed Opt. 2008 May-Jun;13(3):031206
references.pmid: 18601530
references.citation: FASEB J. 2013 Aug;27(8):2927-38
references.pmid: 23616567
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6469-74
references.pmid: 18424559
references.citation: FASEB J. 2013 May;27(5):1808-19
references.pmid: 23195037
references.citation: Hypertension. 2003 Mar;41(3 Pt 2):625-33
references.pmid: 12623970
references.citation: J Am Soc Nephrol. 2012 Aug;23(8):1283-90
references.pmid: 22745476
references.citation: Am J Hypertens. 1997 Jul;10(7 Pt 1):720-7
references.pmid: 9234825
references.citation: Am J Physiol Renal Physiol. 2007 Sep;293(3):F877-84
references.pmid: 17567939
references.citation: Compr Physiol. 2011 Jul;1(3):1075-117
references.pmid: 23733636
references.citation: Ann N Y Acad Sci. 2014 Apr;1311:138-50
references.pmid: 24650277
references.citation: J Biol Chem. 2013 Jan 4;288(1):152-63
references.pmid: 23152498
references.citation: Am J Hypertens. 2011 Jun;24(6):654-60
references.pmid: 21415841
references.citation: Am J Physiol Renal Physiol. 2005 Aug;289(2):F442-50
references.pmid: 15814531
references.citation: Mol Cell Biol. 1998 Dec;18(12):7278-87
references.pmid: 9819414
references.citation: Mol Pharmacol. 2006 Mar;69(3):759-69
references.pmid: 16338988
references.citation: Hypertension. 2002 Dec;40(6):880-5
references.pmid: 12468573
references.citation: J Hypertens. 2009 May;27(5):1033-41
references.pmid: 19293728
references.citation: Commun Integr Biol. 2011 Sep;4(5):528-31
references.pmid: 22046454
references.citation: Curr Opin Nephrol Hypertens. 2012 Jan;21(1):61-5
references.pmid: 22123211
references.citation: Hypertension. 1999 Apr;33(4):1036-42
references.pmid: 10205244
references.citation: Am J Hypertens. 2009 Jul;22(7):770-6
references.pmid: 19373217
references.citation: PLoS One. 2014;9(1):e86713
references.pmid: 24475171
references.citation: Clin Cancer Res. 2006 Dec 1;12(23):6952-9
references.pmid: 17145813