Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Virchows Archiv
Published in: Virchows Archiv 4/2013

01-04-2013 | Original Article

Comprehensive analysis of glomerular mRNA expression of pro- and antithrombotic genes in atypical haemolytic-uremic syndrome (aHUS)

Authors: Friedrich Modde, Putri Andina Agustian, Juliane Wittig, Maximilian Ernst Dämmrich, Vinzent Forstmeier, Udo Vester, Thurid Ahlenstiel, Kerstin Froede, Ulrich Budde, Anne-Margret Wingen, Anke Schwarz, Svjetlana Lovric, Jan Thomas Kielstein, Carsten Bergmann, Nadine Bachmann, Mato Nagel, Hans Heinrich Kreipe, Verena Bröcker, Clemens Luitpold Bockmeyer, Jan Ulrich Becker

Published in: Virchows Archiv | Issue 4/2013

Login to get access

Abstract

Atypical haemolytic–uremic syndrome (aHUS) is, in most cases, due to hereditary or acquired defects in complement regulation and a life-threatening disease. Despite the rapidly grown knowledge about the primary defects in aHUS, the pathogenesis that links complement dysregulation with microthrombus formation in aHUS is still unknown. Thus, we examined the glomerular microvascular expression of pro- and antithrombotic genes. Glomeruli were microdissected from 12 archival paraffin-embedded biopsies with aHUS and from seven control biopsies. Glomerular mRNA expression was quantified by single real-time PCR reactions after preamplification. In addition immunostains were performed for plasminogen activator inhibitor 1 (PAI-1) and for tissue plasminogen activator (tPA). Results were compared between cases and controls and with clinical data. Glomeruli in aHUS had increased mRNA expression of antifibrinolytic, prothrombotic PAI-1, antithrombotic thrombomodulin (THBD) and CD73 and decreased expression of profibrinolytic, antithrombotic tPA compared to controls. Impaired fibrinolysis due to increased microvascular expression of the antifibrinolytic PAI-1 in combination with the decreased expression of the profibrinolytic tPA seems to be a final common pathway in renal thrombotic microangiopathy that is also effective in aHUS. The concomitant induction of antithrombotic transcripts likely indicates counterregulatory efforts, demonstrating that the capillary bed is not a passive victim of complement attack. Future research should investigate if and how complement activation could induce the reported shift in the expression of PAI-1 and tPA.
Literature
1.
Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R (1955) Hämolytisch-urämische Syndrome: Bilaterale Nierenrindennekrosen bei akuten erworbenen hämolytischen Anämien. Schweiz Med Wschr 85:905–909PubMed
2.
Desch K, Motto D (2007) Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolytic–uremic syndrome? J Am Soc Nephrol 18:2457–2460PubMedCrossRef
3.
Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF (2003) Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. J Am Med Assoc 290:1360–1370CrossRef
4.
Taylor CM, Chua C, Howie AJ, Risdon RA (2004) Clinico-pathological findings in diarrhoea-negative haemolytic uraemic syndrome. Pediatr Nephrol 19:419–425PubMedCrossRef
5.
Zhang W, Shi H, Ren H, Shen PY, Pan XX, Li X, Chen YX, Xu YW, Chen XN, Zhu P, Chen N (2009) Clinicopathological characteristics and outcome of Chinese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a 9-year retrospective study. Nephron Clin Pract 112:c177–c183PubMedCrossRef
6.
Karmali MA, Petric M, Lim C, Fleming PC, Arbus GS, Lior H (1985) The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J Infect Dis 151:775–782PubMedCrossRef
7.
Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMed
8.
Proia AD, Harden EA, Silberman HR (1984) Mitomycin-induced hemolytic–uremic syndrome. Arch Pathol Lab Med 108:959–962PubMed
9.
Van Buren D, Van Buren CT, Flechner SM, Maddox AM, Verani R, Kahan BD (1985) De novo hemolytic uremic syndrome in renal transplant recipients immunosuppressed with cyclosporine. Surgery 98:54–62PubMed
10.
11.
Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–4952PubMedCrossRef
12.
Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, Lenk D, Bender BU, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Male DA, Franke G, Zipfel PF (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet 40:676–681PubMedCrossRef
13.
Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46:110–119PubMed
14.
Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A 104:240–245PubMedCrossRef
15.
Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84PubMedCrossRef
16.
Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH (2005) Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:2150–2155PubMedCrossRef
17.
Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCrossRef
18.
Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic–uremic syndrome. N Engl J Med 361:345–357PubMedCrossRef
19.
Stahl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, Karpman D (2009) A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome. Mol Immunol 46:2236–2243PubMedCrossRef
20.
Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563PubMedCrossRef
21.
Skerka C, Jozsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V (2009) Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 101:227–232PubMed
22.
Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome Blood 115:379–387
23.
Virchow RC (1856) Thrombose und Embolie. Gefässentzündung und septische Infektion. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. von Meindinger & Sohn, Frankfurt am Main, pp 219–723
24.
Ghebrehiwet B, Silverberg M, Kaplan AP (1981) Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 153:665–676PubMedCrossRef
25.
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12:682–687PubMedCrossRef
26.
Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y (1997) C5a induces tissue factor activity on endothelial cells. Thromb Haemost 77:394–398PubMed
27.
Wiedmer T, Esmon CT, Sims PJ (1986) Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 68:875–880PubMed
28.
Bergstein JM, Riley M, Bang NU (1992) Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome. N Engl J Med 327:755–759PubMedCrossRef
29.
Sagripanti A, Carpi A, Baicchi U, Morganti M, Rosaia B, Nicolini A, Mittermayer C (1996) Plasmatic parameters of coagulation activation in thrombotic microangiopathy. Biomed Pharmacother 50:357–362PubMedCrossRef
30.
Martin AA, Woolven BL, Harris SJ, Keeley SR, Adams LD, Jureidini KF, Henning PH (2000) Plasminogen activator inhibitor type-1 and interleukin-6 in haemolytic uraemic syndrome. J Paediatr Child Health 36:327–331PubMedCrossRef
31.
Van Geet C, Proesmans W, Arnout J, Vermylen J, Declerck PJ (1998) Activation of both coagulation and fibrinolysis in childhood hemolytic uremic syndrome. Kidney Int 54:1324–1330PubMedCrossRef
32.
Anthony MT, Zeigler ZR, Lister J, Raymond JM, Shadduck RK, Kramer RE, Gryn JF, Rintels PB, Besa EC, George JN, Silver B, Joyce R, Bodensteiner D (1998) Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow transplantation. Am J Hematol 59:9–14PubMedCrossRef
33.
Rondeau E, Mougenot B, Lacave R, Peraldi MN, Kruithof EK, Sraer JD (1990) Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies. Clin Nephrol 33:55–60PubMed
34.
Xu Y, Hagege J, Mougenot B, Sraer JD, Ronne E, Rondeau E (1996) Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney. Kidney Int 50:2011–2019PubMedCrossRef
35.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470PubMed
36.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637PubMedCrossRef
37.
38.
Rijken DC, Lijnen HR (2009) New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 7:4–13PubMedCrossRef
39.
Bergstein JM, Kuederli U, Bang NU (1982) Plasma inhibitor of glomerular fibrinolysis in the hemolytic-uremic syndrome. Am J Med 73:322–327PubMedCrossRef
40.
Slater SC, Ramnath RD, Uttridge K, Saleem MA, Cahill PA, Mathieson PW, Welsh GI, Satchell SC (2012) Chronic exposure to laminar shear stress induces Kruppel-like factor 2 in glomerular endothelial cells and modulates interactions with co-cultured podocytes. Int J Biochem Cell Biol 44:1482–1490PubMedCrossRef
41.
Hershko K, Simhadri V, Blaisdell A, Hunt RC, Newell J, Tseng SC, Hershko AY, Choi JW, Sauna ZE, Wu A, Bram RJ, Komar AA, Kimchi-Sarfaty C (2012) Cyclosporin A impairs the secretion and activity of ADAMTS13 J Biol Chem
42.
43.
Fernandez GC, Te Loo MW, van der Velden TJ, van der Heuvel LP, Palermo MS, Monnens LL (2003) Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome. Pediatr Nephrol 18:1066–1068PubMedCrossRef
44.
Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta A, Pagani C, Noris M, Gobbi M, Stravalaci M, Rottoli D, Tedesco F, Remuzzi G, Zoja C (2011) Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 187:172–180PubMedCrossRef
45.
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265PubMedCrossRef
46.
Deaglio S, Robson SC (2011) Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol 61:301–332PubMedCrossRef
47.
Cvirn G, Gallistl S, Muntean W (2001) Alpha-2-macroglobulin inhibits the anticoagulant action of activated protein C in cord and adult plasma. Haemostasis 31:1–11PubMed
48.
Levi M, Roem D, Kamp AM, de Boer JP, Hack CE, ten Cate JW (1993) Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo. Thromb Haemost 69:141–146PubMed
49.
Meijers JC, Tijburg PN, Bouma BN (1987) Inhibition of human blood coagulation factor Xa by alpha 2-macroglobulin. Biochemistry 26:5932–5937PubMedCrossRef
50.
Downing MR, Bloom JW, Mann KG (1978) Comparison of the inhibition of thrombin by three plasma protease inhibitors. Biochemistry 17:2649–2653PubMedCrossRef
51.
Tiggelman AM, Linthorst C, Boers W, Brand HS, Chamuleau RA (1997) Transforming growth factor-beta-induced collagen synthesis by human liver myofibroblasts is inhibited by alpha2-macroglobulin. J Hepatol 26:1220–1228PubMedCrossRef
52.
Zhang Y, Ge G, Greenspan DS (2006) Inhibition of bone morphogenetic protein 1 by native and altered forms of alpha2-macroglobulin. J Biol Chem 281:39096–39104PubMedCrossRef
53.
Eremina V, Baelde HJ, Quaggin SE (2007) Role of the VEGF—a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 106:p32–p37PubMedCrossRef
54.
Lindgren A, Lindoff C, Norrving B, Astedt B, Johansson BB (1996) Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients. Stroke 27:1066–1071PubMedCrossRef
55.
van Kesteren PJ, Kooistra T, Lansink M, van Kamp GJ, Asscheman H, Gooren LJ, Emeis JJ, Vischer UM, Stehouwer CD (1998) The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost 79:1029–1033PubMed
56.
Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, Horrevoets AJ (2002) Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100:1689–1698PubMedCrossRef
57.
Villarreal G Jr, Zhang Y, Larman HB, Gracia-Sancho J, Koo A, Garcia-Cardena G (2010) Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells. Biochem Biophys Res Commun 391:984–989PubMedCrossRef
58.
Fledderus JO, van Thienen JV, Boon RA, Dekker RJ, Rohlena J, Volger OL, Bijnens AP, Daemen MJ, Kuiper J, van Berkel TJ, Pannekoek H, Horrevoets AJ (2007) Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2. Blood 109:4249–4257PubMedCrossRef
59.
Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone MA Jr, Balasubramanian V, Garcia-Cardena G, Jain MK (2005) Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res 96:e48–e57PubMedCrossRef
60.
Zhang RJ, Yang LH, Zhang Y, Zhou JF, Cao Y, Chen CH (2010) Effect of antisense KLF4 gene on the expression of vWF and PAI-1 in endothelium cells. Zhonghua Xue Ye Xue Za Zhi 31:446–450PubMed
61.
Wojta J, Kaun C, Zorn G, Ghannadan M, Hauswirth AW, Sperr WR, Fritsch G, Printz D, Binder BR, Schatzl G, Zwirner J, Maurer G, Huber K, Valent P (2002) C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood 100:517–523PubMedCrossRef
62.
Kastl SP, Speidl WS, Kaun C, Rega G, Assadian A, Weiss TW, Valent P, Hagmueller GW, Maurer G, Huber K, Wojta J (2006) The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation. J Thromb Haemost 4:1790–1797PubMedCrossRef
Metadata
Title
Comprehensive analysis of glomerular mRNA expression of pro- and antithrombotic genes in atypical haemolytic-uremic syndrome (aHUS)
Authors
Friedrich Modde
Putri Andina Agustian
Juliane Wittig
Maximilian Ernst Dämmrich
Vinzent Forstmeier
Udo Vester
Thurid Ahlenstiel
Kerstin Froede
Ulrich Budde
Anne-Margret Wingen
Anke Schwarz
Svjetlana Lovric
Jan Thomas Kielstein
Carsten Bergmann
Nadine Bachmann
Mato Nagel
Hans Heinrich Kreipe
Verena Bröcker
Clemens Luitpold Bockmeyer
Jan Ulrich Becker
Publication date
01-04-2013
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 4/2013
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-013-1386-4

Other articles of this Issue 4/2013

Virchows Archiv 4/2013 Go to the issue

Original Article

Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression

Original Article

Brain metastases from papillary thyroid carcinomas

Original Article

Mature T/NK-cell lymphoproliferative disease and Epstein–Barr virus infection are more frequent in patients with rheumatoid arthritis treated with methotrexate

Original Article

Detection of HPV infection in head and neck squamous cell carcinoma: a practical proposal

Original Article

Low RKIP expression associates with poor prognosis in bladder cancer patients

Invited Commentary

The rise and fall of the autopsy