Activity-based protein profiling guided identification of urine proteinase 3 activity in subclinical rejection after renal transplantation

Springer Science and Business Media LLC - Tập 17 Số 1 - 2020
Mario Navarrete1, Brice Korkmaz2, Carla Guarino2, Adam Lesner3, Ying Lao1, Julie Ho1, Peter Nickerson1, John A. Wilkins4
1Manitoba Centre for Proteomics and Systems Biology, 799 John Buhler Research Centre, 715 McDermot Ave., Winnipeg, MB, R3E3P4, Canada
2INSERM, UMR 1100, “Centre d’Etude des Pathologies Respiratoires”, Université de Tours, 37032, Tours, France
3Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland
4Section Biomedical Proteomics, Dept. Internal Medicine, University of Manitoba, Winnipeg, MB, Canada

Tóm tắt

Abstract Background The pathophysiology of subclinical versus clinical rejection remains incompletely understood given their equivalent histological severity but discordant graft function. The goal was to evaluate serine hydrolase enzyme activities to explore if there were any underlying differences in activities during subclinical versus clinical rejection. Methods Serine hydrolase activity-based protein profiling (ABPP) was performed on the urines of a case control cohort of patients with biopsy confirmed subclinical or clinical transplant rejection. In-gel analysis and affinity purification with mass spectrometry were used to demonstrate and identify active serine hydrolase activity. An assay for proteinase 3 (PR3/PRTN3) was adapted for the quantitation of activity in urine. Results In-gel ABPP profiles suggested increased intensity and diversity of serine hydrolase activities in urine from patients undergoing subclinical versus clinical rejection. Serine hydrolases (n = 30) were identified by mass spectrometry in subclinical and clinical rejection patients with 4 non-overlapping candidates between the two groups (i.e. ABHD14B, LTF, PR3/PRTN3 and PRSS12). Western blot and the use of a specific inhibitor confirmed the presence of active PR3/PRTN3 in samples from patients undergoing subclinical rejection. Analysis of samples from normal donors or from several serial post-transplant urines indicated that although PR3/PRTN3 activity may be highly associated with low-grade subclinical inflammation, the enzyme activity was not restricted to this patient group. Conclusions There appear to be limited qualitative and quantitative differences in serine hydrolase activity in patients with subclinical versus clinical renal transplant rejection. The majority of enzymes identified were present in samples from both groups implying that in-gel quantitative differences may largely relate to the activity status of shared enzymes. However qualitative compositional differences were also observed indicating differential activities. The PR3/PRTN3 analyses indicate that the activity status of urine in transplant patients is dynamic possibly reflecting changes in the underlying processes in the transplant. These data suggest that differential serine hydrolase pathways may be active in subclinical versus clinical rejection which requires further exploration in larger patient cohorts. Although this study focused on PR3/PRTN3, this does not preclude the possibility that other enzymes may play critical roles in the rejection process.

Từ khóa


Tài liệu tham khảo

Menon MC, Murphy B, Heeger PS. Moving biomarkers toward clinical implementation in kidney transplantation. J Am Soc Nephrol. 2017;28(3):735–47.

Naesens M, Anglicheau D. Precision transplant medicine: biomarkers to the rescue. J Am Soc Nephrol. 2018;29(1):24–34.

Hirt-Minkowski P, De Serres SA, Ho J. Developing renal allograft surveillance strategies—urinary biomarkers of cellular rejection. Can J Kidney Health Dis. 2015;2:28.

Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349(24):2326–33.

Nickerson P, Jeffery J, Gough J, McKenna R, Grimm P, Cheang M, et al. Identification of clinical and histopathologic risk factors for diminished renal function 2 years posttransplant. J Am Soc Nephrol. 1998;9(3):482–7.

Grimm PC, Nickerson P, Gough J, McKenna R, Stern E, Jeffery J, et al. Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol. 2003;14(6):1662–8.

Cosio FG, Grande JP, Wadei H, Larson TS, Griffin MD, Stegall MD. Predicting subsequent decline in kidney allograft function from early surveillance biopsies. Am J Transplant. 2005;5(10):2464–72.

Cosio FG, El Ters M, Cornell LD, Schinstock CA, Stegall MD. Changing kidney allograft histology early post transplant: prognostic Implications of 1-year protocol biopsies. Am J Transplant. 2016;16(1):194–203.

Moreso F, Ibernon M, Goma M, Carrera M, Fulladosa X, Hueso M, et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant. 2006;6(4):747–52.

Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol. 1998;9(11):2129–34.

Kurtkoti J, Sakhuja V, Sud K, Minz M, Nada R, Kohli HS, et al. The utility of 1- and 3-month protocol biopsies on renal allograft function: a randomized controlled study. Am J Transplant. 2008;8(2):317–23.

Loupy A, Vernerey D, Tinel C, Aubert O, van Duong Huyen JP, Rabant M, et al. Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts. J Am Soc Nephrol. 2015;26(7):1721–31.

Kurian SM, Velazquez E, Thompson R, Whisenant T, Rose S, Riley N, et al. Orthogonal comparison of molecular signatures of kidney transplants with subclinical and clinical acute rejection: equivalent performance is agnostic to both technology and platform. Am J Transplant. 2017;17(8):2103–16.

Rush D, Arlen D, Boucher A, Busque S, Cockfield SM, Girardin C, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant. 2007;7(11):2538–45.

Hruba P, Brabcova I, Gueler F, Krejcik Z, Stranecky V, Svobodova E, et al. Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes. Kidney Int. 2015;88(4):785–95.

Zhang W, Yi Z, Keung KL, Shang H, Wei C, Cravedi P, et al. A peripheral blood gene expression signature to diagnose subclinical acute rejection. J Am Soc Nephrol. 2019;30(8):1481–94.

Schaub S, Rush D, Wilkins J, Gibson IW, Weiler T, Sangster K, et al. Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol. 2004;15(1):219–27.

Ho J, Rush DN, Krokhin O, Antonovici M, Gao A, Bestland J, et al. Elevated urinary matrix metalloproteinase-7 detects underlying renal allograft inflammation and injury. Transplantation. 2016;100(3):648–54.

Ho J, Sharma A, Mandal R, Wishart DS, Wiebe C, Storsley L, et al. Detecting renal allograft inflammation using quantitative urine metabolomics and CXCL10. Transplant Direct. 2016;2(6):e78.

Sigdel TK, Gao Y, He J, Wang A, Nicora CD, Fillmore TL, et al. Mining the human urine proteome for monitoring renal transplant injury. Kidney Int. 2016;89(6):1244–52.

Liu Y, Patricelli MP, Cravatt BF. Activity-based protein profiling: the serine hydrolases. Proc Natl Acad Sci USA. 1999;96(26):14694–9.

Navarrete M, Wilkins JA, Lao Y, Rush DN, Nickerson PW, Ho J. Activity-based protein profiling approaches for transplantation. Transplantation. 2019;103:1790–8.

Ho J, Hirt-Minkowski P, Wilkins JA. New developments in transplant proteomics. Curr Opin Nephrol Hypertens. 2017;26(3):229–34.

UniProt Consortium T. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2018;46(5):2699.

Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res. 2018;46(D1):D624–32.

Bachovchin DA, Cravatt BF. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov. 2012;11(1):52–68.

Korkmaz B, Attucci S, Juliano MA, Kalupov T, Jourdan ML, Juliano L, et al. Measuring elastase, proteinase 3 and cathepsin G activities at the surface of human neutrophils with fluorescence resonance energy transfer substrates. Nat Protoc. 2008;3(6):991–1000.

Guarino C, Gruba N, Grzywa R, Dyguda-Kazimierowicz E, Hamon Y, Legowska M, et al. Exploiting the S4-S5 specificity of human neutrophil proteinase 3 to improve the potency of peptidyl di(chlorophenyl)-phosphonate ester inhibitors: a kinetic and molecular modeling analysis. J Med Chem. 2018;61(5):1858–70.

Navarrete M, Ho J, Dwivedi RC, Choi N, Ezzati P, Spicer V, et al. Activity-based protein profiling of intraoperative serine hydrolase activities during cardiac surgery. J Proteome Res. 2018;17(10):3547–56.

Navarrete M, Ho J, Krokhin O, Ezzati P, Rigatto C, Reslerova M, et al. Proteomic characterization of serine hydrolase activity and composition in normal urine. Clin Proteomics. 2013;10(1):17.

Navarrete M, Ho J, Dwivedi RC, Choi N, Ezzati P, Spicer V, et al. Activity-based protein profiling of intraoperative serine hydrolase activities during cardiac surgery. J Proteome Res. 2018;17:3547–56.

Ho J, Rush DN, Gibson IW, Karpinski M, Storsley L, Bestland J, et al. Early urinary CCL2 is associated with the later development of interstitial fibrosis and tubular atrophy in renal allografts. Transplantation. 2010;90(4):394–400.

Ho J, Wiebe C, Gibson IW, Hombach-Klonisch S, Gao A, Rigatto C, et al. Elevated urinary CCL2: Cr at 6 months is associated with renal allograft interstitial fibrosis and inflammation at 24 months. Transplantation. 2014;98(1):39–46.

Padmanabhan B, Kuzuhara T, Adachi N, Horikoshi M. The crystal structure of CCG1/TAF(II)250-interacting factor B (CIB). J Biol Chem. 2004;279(10):9615–24.

Rajendran A, Vaidya K, Mendoza J, Bridwell-Rabb J, Kamat SS. Functional annotation of ABHD14B, an orphan serine hydrolase enzyme. Biochemistry. 2020;59(2):183–96.

Kruzel ML, Zimecki M, Actor JK. Lactoferrin in a context of inflammation-induced pathology. Front Immunol. 2017;8:1438.

Massucci MT, Giansanti F, Di Nino G, Turacchio M, Giardi MF, Botti D, et al. Proteolytic activity of bovine lactoferrin. Biometals. 2004;17(3):249–55.

Daryadel A, Haubitz M, Figueiredo M, Steubl D, Roos M, Mader A, et al. The C-terminal fragment of agrin (CAF), a novel marker of renal function, is filtered by the kidney and reabsorbed by the proximal tubule. PLoS ONE. 2016;11(7):e0157905.

Halloran PF, Venner JM, Madill-Thomsen KS, Einecke G, Parkes MD, Hidalgo LG, et al. Review: The transcripts associated with organ allograft rejection. Am J Transplant. 2018;18(4):785–95.

Kettritz R. Neutral serine proteases of neutrophils. Immunol Rev. 2016;273(1):232–48.

Crisford H, Sapey E, Stockley RA. Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases. Respir Res. 2018;19(1):180.

Twigg MS, Brockbank S, Lowry P, FitzGerald SP, Taggart C, Weldon S. The role of serine proteases and antiproteases in the cystic fibrosis lung. Mediat Inflamm. 2015;2015:293053.

Clancy DM, Henry CM, Sullivan GP, Martin SJ. Neutrophil extracellular traps can serve as platforms for processing and activation of IL-1 family cytokines. FEBS J. 2017;284(11):1712–25.

Reumaux D, Hordijk PL, Duthilleul P, Roos D. Priming by tumor necrosis factor-alpha of human neutrophil NADPH-oxidase activity induced by anti-proteinase-3 or anti-myeloperoxidase antibodies. J Leukoc Biol. 2006;80(6):1424–33.

Tati R, Kristoffersson AC, Manea Hedstrom M, Morgelin M, Wieslander J, van Kooten C, et al. Neutrophil protease cleavage of Von Willebrand factor in glomeruli—an anti-thrombotic mechanism in the kidney. EBioMedicine. 2017;16:302–11.

Kuravi SJ, Bevins A, Satchell SC, Harper L, Williams JM, Rainger GE, et al. Neutrophil serine proteases mediate inflammatory cell recruitment by glomerular endothelium and progression towards dysfunction. Nephrol Dial Transplant. 2012;27(12):4331–8.

Grimm PC, McKenna R, Nickerson P, Russell ME, Gough J, Gospodarek E, et al. Clinical rejection is distinguished from subclinical rejection by increased infiltration by a population of activated macrophages. J Am Soc Nephrol. 1999;10(7):1582–9.

Musante L, Tataruch D, Gu D, Liu X, Forsblom C, Groop PH, et al. Proteases and protease inhibitors of urinary extracellular vesicles in diabetic nephropathy. J Diabetes Res. 2015;2015:289734.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 17 Số 1

Thông tin tác giả