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. 2003 Dec;4(6):571–583. doi: 10.1002/cfg.347

Gene Expression Profiling on Global cDNA Arrays Gives Hints Concerning Potential Signal Transduction Pathways Involved in Cardiac Fibrosis of Renal Failure

Kerstin Amann 1,✉, Heidrun Ridinger 2, Christiane Rutenberg 2, Eberhard Ritz 3, Gerhard Mall 4, Christian Maercker 2
PMCID: PMC2447303  PMID: 18629021

Abstract

Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague–Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart-specific gene expression profiling, with RZPD Rat Unigene-1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non-vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin–angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and Gproteins (short-term signalling); and (b) via motor proteins, actins and integrins (longterm signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi-bin/services/exp/viewExpressionData.pl.cgi

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Selected References

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  1. Amann K., Breitbach M., Ritz E., Mall G. Myocyte/capillary mismatch in the heart of uremic patients. J Am Soc Nephrol. 1998 Jun;9(6):1018–1022. doi: 10.1681/ASN.V961018. [DOI] [PubMed] [Google Scholar]
  2. Amann K., Koch A., Hofstetter J., Gross M. L., Haas C., Orth S. R., Ehmke H., Rump L. C., Ritz E. Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers. Kidney Int. 2001 Oct;60(4):1309–1323. doi: 10.1046/j.1523-1755.2001.00936.x. [DOI] [PubMed] [Google Scholar]
  3. Amann K., Kronenberg G., Gehlen F., Wessels S., Orth S., Münter K., Ehmke H., Mall G., Ritz E. Cardiac remodelling in experimental renal failure--an immunohistochemical study. Nephrol Dial Transplant. 1998 Aug;13(8):1958–1966. doi: 10.1093/ndt/13.8.1958. [DOI] [PubMed] [Google Scholar]
  4. Amann K., Münter K., Wessels S., Wagner J., Balajew V., Hergenröder S., Mall G., Ritz E. Endothelin A receptor blockade prevents capillary/myocyte mismatch in the heart of uremic animals. J Am Soc Nephrol. 2000 Sep;11(9):1702–1711. doi: 10.1681/ASN.V1191702. [DOI] [PubMed] [Google Scholar]
  5. Amann K., Neimeier K. A., Schwarz U., Törnig J., Matthias S., Orth S. R., Mall G., Ritz E. Rats with moderate renal failure show capillary deficit in heart but not skeletal muscle. Am J Kidney Dis. 1997 Sep;30(3):382–388. doi: 10.1016/s0272-6386(97)90283-3. [DOI] [PubMed] [Google Scholar]
  6. Amann K., Ritz E. Cardiac disease in chronic uremia: pathophysiology. Adv Ren Replace Ther. 1997 Jul;4(3):212–224. doi: 10.1016/s1073-4449(97)70030-x. [DOI] [PubMed] [Google Scholar]
  7. Amann K., Ritz E., Wiest G., Klaus G., Mall G. A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. J Am Soc Nephrol. 1994 Apr;4(10):1814–1819. doi: 10.1681/ASN.V4101814. [DOI] [PubMed] [Google Scholar]
  8. Boer J. M., Huber W. K., Sültmann H., Wilmer F., von Heydebreck A., Haas S., Korn B., Gunawan B., Vente A., Füzesi L. Identification and classification of differentially expressed genes in renal cell carcinoma by expression profiling on a global human 31,500-element cDNA array. Genome Res. 2001 Nov;11(11):1861–1870. doi: 10.1101/gr.184501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brilla C. G. Renin-angiotensin-aldosterone system and myocardial fibrosis. Cardiovasc Res. 2000 Jul;47(1):1–3. doi: 10.1016/s0008-6363(00)00092-4. [DOI] [PubMed] [Google Scholar]
  10. Brown Nancy J., Vaughan Douglas E., Fogo Agnes B. Aldosterone and PAI-1: implications for renal injury. J Nephrol. 2002 May-Jun;15(3):230–235. [PubMed] [Google Scholar]
  11. Burridge K., Chrzanowska-Wodnicka M. Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol. 1996;12:463–518. doi: 10.1146/annurev.cellbio.12.1.463. [DOI] [PubMed] [Google Scholar]
  12. Cau J., Faure S., Comps M., Delsert C., Morin N. A novel p21-activated kinase binds the actin and microtubule networks and induces microtubule stabilization. J Cell Biol. 2001 Dec 10;155(6):1029–1042. doi: 10.1083/jcb.200104123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chakraborti T., Mandal A., Mandal M., Das S., Chakraborti S. Complement activation in heart diseases. Role of oxidants. Cell Signal. 2000 Oct;12(9-10):607–617. doi: 10.1016/s0898-6568(00)00111-x. [DOI] [PubMed] [Google Scholar]
  14. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  15. Chrzanowska-Wodnicka M., Burridge K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol. 1996 Jun;133(6):1403–1415. doi: 10.1083/jcb.133.6.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Douglas S. A., Ohlstein E. H. Signal transduction mechanisms mediating the vascular actions of endothelin. J Vasc Res. 1997 May-Jun;34(3):152–164. doi: 10.1159/000159219. [DOI] [PubMed] [Google Scholar]
  17. Esenabhalu Victor E., Cerimagic Mirza, Malli Roland, Osibow Karin, Levak-Frank Sanja, Frieden Maud, Sattler Wolfgang, Kostner Gerhard M., Zechner Rudolf, Graier Wolfgang F. Tissue-specific expression of human lipoprotein lipase in the vascular system affects vascular reactivity in transgenic mice. Br J Pharmacol. 2002 Jan;135(1):143–154. doi: 10.1038/sj.bjp.0704440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ewart H. S., Carroll R., Severson D. L. Lipoprotein lipase activity is stimulated by insulin and dexamethasone in cardiomyocytes from diabetic rats. Can J Physiol Pharmacol. 1999 Aug;77(8):571–578. [PubMed] [Google Scholar]
  19. Fisicaro N., Aminian A., Hinchliffe S. J., Morgan B. P., Pearse M. J., D'Apice A. J., Cowan P. J. The pig analogue of CD59 protects transgenic mouse hearts from injury by human complement. Transplantation. 2000 Sep 27;70(6):963–968. doi: 10.1097/00007890-200009270-00014. [DOI] [PubMed] [Google Scholar]
  20. Giulumian Ararat D., Molero Mariela M., Reddy Vikram B., Pollock Jennifer S., Pollock David M., Fuchs Leslie C. Role of ET-1 receptor binding and [Ca(2+)](i) in contraction of coronary arteries from DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1944–H1949. doi: 10.1152/ajpheart.00627.2001. [DOI] [PubMed] [Google Scholar]
  21. Hartwig J. H., Bokoch G. M., Carpenter C. L., Janmey P. A., Taylor L. A., Toker A., Stossel T. P. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell. 1995 Aug 25;82(4):643–653. doi: 10.1016/0092-8674(95)90036-5. [DOI] [PubMed] [Google Scholar]
  22. Hwang D. M., Dempsey A. A., Lee C. Y., Liew C. C. Identification of differentially expressed genes in cardiac hypertrophy by analysis of expressed sequence tags. Genomics. 2000 May 15;66(1):1–14. doi: 10.1006/geno.2000.6171. [DOI] [PubMed] [Google Scholar]
  23. Hwang Juey-Jen, Allen Paul D., Tseng George C., Lam Ching-Wan, Fananapazir Lameh, Dzau Victor J., Liew Choong-Chin. Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure. Physiol Genomics. 2002 Jul 12;10(1):31–44. doi: 10.1152/physiolgenomics.00122.2001. [DOI] [PubMed] [Google Scholar]
  24. Ishikawa Y., Akasaka Y., Ishii T., Itoh K., Masuda T., Zhang L., Kiguchi H. Sequential changes in localization of repair-related proteins (heat shock protein 70, ubiquitin and vascular endothelial growth factor) in the different stages of myocardial infarction. Histopathology. 2000 Dec;37(6):546–554. doi: 10.1046/j.1365-2559.2000.00994.x. [DOI] [PubMed] [Google Scholar]
  25. Keely P. J., Westwick J. K., Whitehead I. P., Der C. J., Parise L. V. Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature. 1997 Dec 11;390(6660):632–636. doi: 10.1038/37656. [DOI] [PubMed] [Google Scholar]
  26. Khurana Bharat, Khurana Taruna, Khaire Nandkumar, Noegel Angelika A. Functions of LIM proteins in cell polarity and chemotactic motility. EMBO J. 2002 Oct 15;21(20):5331–5342. doi: 10.1093/emboj/cdf550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kirchhoff S. R., Gupta S., Knowlton A. A. Cytosolic heat shock protein 60, apoptosis, and myocardial injury. Circulation. 2002 Jun 18;105(24):2899–2904. doi: 10.1161/01.cir.0000019403.35847.23. [DOI] [PubMed] [Google Scholar]
  28. Krendel Mira, Zenke Frank T., Bokoch Gary M. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol. 2002 Apr;4(4):294–301. doi: 10.1038/ncb773. [DOI] [PubMed] [Google Scholar]
  29. Kuźnicki J., Kordowska J., Puzianowska M., Woźniewicz B. M. Calcyclin as a marker of human epithelial cells and fibroblasts. Exp Cell Res. 1992 Jun;200(2):425–430. doi: 10.1016/0014-4827(92)90191-a. [DOI] [PubMed] [Google Scholar]
  30. Leung T., Chen X. Q., Tan I., Manser E., Lim L. Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization. Mol Cell Biol. 1998 Jan;18(1):130–140. doi: 10.1128/mcb.18.1.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lin K. M., Lin B., Lian I. Y., Mestril R., Scheffler I. E., Dillmann W. H. Combined and individual mitochondrial HSP60 and HSP10 expression in cardiac myocytes protects mitochondrial function and prevents apoptotic cell deaths induced by simulated ischemia-reoxygenation. Circulation. 2001 Apr 3;103(13):1787–1792. doi: 10.1161/01.cir.103.13.1787. [DOI] [PubMed] [Google Scholar]
  32. Mall G., Huther W., Schneider J., Lundin P., Ritz E. Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol Dial Transplant. 1990;5(1):39–44. doi: 10.1093/ndt/5.1.39. [DOI] [PubMed] [Google Scholar]
  33. McMahon Aisling C., Greenwald Stephen E., Dodd Susan M., Hurst Martin J., Raine Anthony E. G. Prolonged calcium transients and myocardial remodelling in early experimental uraemia. Nephrol Dial Transplant. 2002 May;17(5):759–764. doi: 10.1093/ndt/17.5.759. [DOI] [PubMed] [Google Scholar]
  34. Nabokov A. V., Amann K., Wessels S., Münter K., Wagner J., Ritz E. Endothelin receptor antagonists influence cardiovascular morphology in uremic rats. Kidney Int. 1999 Feb;55(2):512–519. doi: 10.1046/j.1523-1755.1999.00290.x. [DOI] [PubMed] [Google Scholar]
  35. Nambi P., Clozel M., Feuerstein G. Endothelin and heart failure. Heart Fail Rev. 2001 Dec;6(4):335–340. doi: 10.1023/a:1011464510857. [DOI] [PubMed] [Google Scholar]
  36. Naujokat Cord, Hoffmann Stephan. Role and function of the 26S proteasome in proliferation and apoptosis. Lab Invest. 2002 Aug;82(8):965–980. doi: 10.1097/01.lab.0000022226.23741.37. [DOI] [PubMed] [Google Scholar]
  37. Oakley C., Brunette D. M. Topographic compensation: guidance and directed locomotion of fibroblasts on grooved micromachined substrata in the absence of microtubules. Cell Motil Cytoskeleton. 1995;31(1):45–58. doi: 10.1002/cm.970310106. [DOI] [PubMed] [Google Scholar]
  38. Papakonstantinou E., Roth M., Kokkas B., Papadopoulos C., Karakiulakis G. Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. J Cardiovasc Pharmacol. 2001 Nov;38(5):715–728. doi: 10.1097/00005344-200111000-00008. [DOI] [PubMed] [Google Scholar]
  39. Parfrey P. S., Foley R. N., Harnett J. D., Kent G. M., Murray D. C., Barre P. E. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant. 1996 Jul;11(7):1277–1285. [PubMed] [Google Scholar]
  40. Raine A. E., Margreiter R., Brunner F. P., Ehrich J. H., Geerlings W., Landais P., Loirat C., Mallick N. P., Selwood N. H., Tufveson G. Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant. 1992;7 (Suppl 2):7–35. [PubMed] [Google Scholar]
  41. Rodrigues B., Cam M. C., Jian K., Lim F., Sambandam N., Shepherd G. Differential effects of streptozotocin-induced diabetes on cardiac lipoprotein lipase activity. Diabetes. 1997 Aug;46(8):1346–1353. doi: 10.2337/diab.46.8.1346. [DOI] [PubMed] [Google Scholar]
  42. Ruilope L. M., van Veldhuisen D. J., Ritz E., Luscher T. F. Renal function: the Cinderella of cardiovascular risk profile. J Am Coll Cardiol. 2001 Dec;38(7):1782–1787. doi: 10.1016/s0735-1097(01)01627-8. [DOI] [PubMed] [Google Scholar]
  43. Schoenwaelder S. M., Burridge K. Bidirectional signaling between the cytoskeleton and integrins. Curr Opin Cell Biol. 1999 Apr;11(2):274–286. doi: 10.1016/s0955-0674(99)80037-4. [DOI] [PubMed] [Google Scholar]
  44. Sharma H. S., Stahl J., Weisensee D., Löw-Friedrich I. Cytoprotective mechanisms in cultured cardiomyocytes. Mol Cell Biochem. 1996 Jul-Aug;160-161:217–224. doi: 10.1007/BF00240052. [DOI] [PubMed] [Google Scholar]
  45. Stefanski A., Schmidt K. G., Waldherr R., Ritz E. Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis. Kidney Int. 1996 Oct;50(4):1321–1326. doi: 10.1038/ki.1996.444. [DOI] [PubMed] [Google Scholar]
  46. Tsuruda Toshihiro, Jougasaki Michihisa, Boerrigter Guido, Huntley Brenda K., Chen Horng H., D'Assoro Antonino B., Lee Shang C., Larsen Amy M., Cataliotti Alessandro, Burnett John C., Jr Cardiotrophin-1 stimulation of cardiac fibroblast growth: roles for glycoprotein 130/leukemia inhibitory factor receptor and the endothelin type A receptor. Circ Res. 2002 Feb 8;90(2):128–134. doi: 10.1161/hh0202.103613. [DOI] [PubMed] [Google Scholar]
  47. Venugopal B., Sharon R., Abramovitz R., Khasin A., Miskin R. Plasminogen activator inhibitor-1 in cardiovascular cells: rapid induction after injecting mice with kainate or adrenergic agents. Cardiovasc Res. 2001 Feb 1;49(2):476–483. doi: 10.1016/s0008-6363(00)00271-6. [DOI] [PubMed] [Google Scholar]
  48. Väkevä A., Laurila P., Meri S. Loss of expression of protectin (CD59) is associated with complement membrane attack complex deposition in myocardial infarction. Lab Invest. 1992 Nov;67(5):608–616. [PubMed] [Google Scholar]
  49. Väkevä A., Morgan B. P., Tikkanen I., Helin K., Laurila P., Meri S. Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium. Am J Pathol. 1994 Jun;144(6):1357–1368. [PMC free article] [PubMed] [Google Scholar]
  50. Wilson K., Fry G. L., Chappell D. A., Sigmund C. D., Medh J. D. Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein e knockout mice but not in C57BL/6 mice. Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1809–1815. doi: 10.1161/hq1101.097805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zolk Oliver, Quattek Jessika, Seeland Ute, El-Armouche Ali, Eschenhagen Thomas, Böhm Michael. Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats. Cardiovasc Res. 2002 Feb 1;53(2):363–371. doi: 10.1016/s0008-6363(01)00468-0. [DOI] [PubMed] [Google Scholar]

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