Urine Angiotensin II Signature Proteins as Markers of Fibrosis in Kidney Transplant Recipients.
ADP-ribosyl Cyclase
/ urine
Adult
Angiotensin II
/ metabolism
Antigens, CD
/ urine
Biomarkers
/ urine
Case-Control Studies
Female
Fibrosis
GPI-Linked Proteins
/ urine
Glutamate-Ammonia Ligase
/ urine
Humans
Kidney
/ metabolism
Kidney Diseases
/ etiology
Kidney Transplantation
/ adverse effects
Laminin
/ urine
Male
Mass Spectrometry
Middle Aged
Predictive Value of Tests
Thiolester Hydrolases
/ urine
Thrombospondin 1
/ urine
Treatment Outcome
Urinalysis
rhoB GTP-Binding Protein
/ urine
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
pubmed:
26
2
2019
medline:
26
5
2020
entrez:
26
2
2019
Statut:
ppublish
Résumé
Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide antifibrotic therapy are lacking. Using angiotensin II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry-based assays for quantification of 6 AngII signature proteins (bone marrow stromal cell antigen 1, glutamine synthetase [GLNA], laminin subunit beta-2, lysophospholipase I, ras homolog family member B, and thrombospondin-I [TSP1]) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients. Urine excretion of 6 AngII-regulated proteins was quantified using selected reaction monitoring and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies. The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared with 20 matched controls with no IFTA (mean log2[fmol/µmol of creatinine], bone marrow stromal cell antigen 1: 3.8 versus 3.0, P = 0.03; GLNA: 1.2 versus -0.4, P = 0.03; laminin subunit beta-2: 6.1 versus 5.4, P = 0.06; lysophospholipase I: 2.1 versus 0.6, P = 0.002; ras homolog family member B: 1.2 versus -0.1, P = 0.006; TSP1_GGV: 2.5 versus 1.9; P = 0.15; and TSP1_TIV: 2.0 versus 0.6, P = 0.0006). Receiver operating characteristic curve analysis demonstrated an area under the curve = 0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic IFTA and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors (P < 0.05). AngII-regulated proteins may represent markers of IFTA and guide antifibrotic therapies.
Sections du résumé
BACKGROUND
Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide antifibrotic therapy are lacking. Using angiotensin II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry-based assays for quantification of 6 AngII signature proteins (bone marrow stromal cell antigen 1, glutamine synthetase [GLNA], laminin subunit beta-2, lysophospholipase I, ras homolog family member B, and thrombospondin-I [TSP1]) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients.
METHODS
Urine excretion of 6 AngII-regulated proteins was quantified using selected reaction monitoring and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies.
RESULTS
The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared with 20 matched controls with no IFTA (mean log2[fmol/µmol of creatinine], bone marrow stromal cell antigen 1: 3.8 versus 3.0, P = 0.03; GLNA: 1.2 versus -0.4, P = 0.03; laminin subunit beta-2: 6.1 versus 5.4, P = 0.06; lysophospholipase I: 2.1 versus 0.6, P = 0.002; ras homolog family member B: 1.2 versus -0.1, P = 0.006; TSP1_GGV: 2.5 versus 1.9; P = 0.15; and TSP1_TIV: 2.0 versus 0.6, P = 0.0006). Receiver operating characteristic curve analysis demonstrated an area under the curve = 0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic IFTA and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors (P < 0.05).
CONCLUSIONS
AngII-regulated proteins may represent markers of IFTA and guide antifibrotic therapies.
Identifiants
pubmed: 30801542
doi: 10.1097/TP.0000000000002676
doi:
Substances chimiques
Antigens, CD
0
Biomarkers
0
GPI-Linked Proteins
0
Laminin
0
RHOB protein, human
0
Thrombospondin 1
0
thrombospondin-1, human
0
Angiotensin II
11128-99-7
laminin beta2
124148-86-3
LYPLA1 protein, human
EC 3.1.2.-
Thiolester Hydrolases
EC 3.1.2.-
ADP-ribosyl Cyclase
EC 3.2.2.5
ADP-ribosyl cyclase 2
EC 3.2.2.5
rhoB GTP-Binding Protein
EC 3.6.5.2
glutamine synthetase I
EC 6.3.1.-
Glutamate-Ammonia Ligase
EC 6.3.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e146-e158Subventions
Organisme : CIHR
Pays : Canada
Commentaires et corrections
Type : CommentIn