title: Identification of Biomarkers for PKD1 Using Urinary Exosomes.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either PKD1 or PKD2, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 are secreted on urinary exosome-like vesicles (ELVs) (100-nm diameter vesicles), in which PC1 is present in a cleaved form and may be complexed with PC2. Here, label-free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 individuals with PKD1 mutations and 18 normal controls) revealed that of 2008 ELV proteins, 9 (0.32%) were expressed at significantly different levels in samples from individuals with PKD1 mutations compared to controls (P<0.03). In samples from individuals with PKD1 mutations, levels of PC1 and PC2 were reduced to 54% (P<0.02) and 53% (P<0.001), respectively. Transmembrane protein 2 (TMEM2), a protein with homology to fibrocystin, was 2.1-fold higher in individuals with PKD1 mutations (P<0.03). The PC1/TMEM2 ratio correlated inversely with height-adjusted total kidney volume in the discovery cohort, and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish individuals with PKD1 mutations from controls in a confirmation cohort. In summary, results of this study suggest that a test measuring the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in diagnosis and monitoring of polycystic kidney disease. Future studies will focus on increasing sample size and confirming these studies. The data were deposited in the ProteomeXchange (identifier PXD001075).
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Hogan
authors.affiliation: Division of Nephrology and Hypertension, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Bakeberg
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Vladimir G
authors.initials: VG
authors.lastname: Gainullin
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Irazabal
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: Harmon
authors.affiliation: Renal Laboratory, Department of Laboratory Medicine and Pathology, and.
authors.forename: John C
authors.initials: JC
authors.lastname: Lieske
authors.affiliation: Medical Genome Facility-Proteomics Core, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: M Cristine
authors.initials: MC
authors.lastname: Charlesworth
authors.affiliation: Medical Genome Facility-Proteomics Core, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Johnson
authors.affiliation: Medical Genome Facility-Proteomics Core, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Madden
authors.affiliation: Medical Genome Facility-Proteomics Core, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Roman M
authors.initials: RM
authors.lastname: Zenka
authors.affiliation: Medical Genome Facility-Proteomics Core, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McCormick
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sundsbak
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Heyer
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Division of Nephrology and Hypertension.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.affiliation: Division of Nephrology and Hypertension, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas cward6@kumc.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ward
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D055354:Exosomes / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012016:Reference Values; D012680:Sensitivity and Specificity; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D016482:Urinalysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D050396:TRPP Cation Channels
keywords: ADPKD; genetic renal disease; polycystic kidney disease