title: Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism.
abstract: BACKGROUND
  The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase.
  
  
  OBJECTIVE
  To uncover renin-angiotensin system-independent functions of the (P)RR.
  
  
  RESULTS
  We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1.
  
  
  CONCLUSIONS
  Our study identifies a renin-angiotensin system-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor.
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Nelson
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sorrentino
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: Loregger
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Monique T
authors.initials: MT
authors.lastname: Mulder
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jeroen A A
authors.initials: JA
authors.lastname: Demmers
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Geesje
authors.initials: G
authors.lastname: M-Dallinga-Thie
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands. a.danser@erasmusmc.nl n.zelcer@amc.uva.nl.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.affiliation: From the Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Medical Center, Shenzhen University, Shenzhen, China (X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (X.L., M.E.M., M.T.M., A.H.J.D.) and Proteomics Center (D.H.W.D., J.A.A.D.), Erasmus Medical Center, Rotterdam, The Netherlands; and Department of Medical Biochemistry (X.L., J.K.N., V.S., A.L., S.S., N.Z.) and Laboratory of Experimental Vascular Medicine (G.M.D-.T.), Academic Medical Center, Amsterdam, The Netherlands. a.danser@erasmusmc.nl n.zelcer@amc.uva.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D047369:Chromatin Immunoprecipitation; D003412:Cricetulus; D004705:Endocytosis; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin; D000093342:Prorenin Receptor
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D025262:Vacuolar Proton-Translocating ATPases; D000099183:Sortilin; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C573412:LDLR protein, human
keywords: LDL receptors; cholesterol homeostasis; endocytosis; renin–angiotensin system; sortilin