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Calcineurin inhibitors and immunosuppression – a tale of two isoforms

Published online by Cambridge University Press:  04 July 2012

Clintoria R. Williams  and
Jennifer L. Gooch
Clintoria R. Williams
Affiliation:
Department of Medicine, Division of Nephrology, Emory University School of Medicine, Atlanta, GA, USA
Jennifer L. Gooch*
Affiliation:
Department of Medicine, Division of Nephrology, Emory University School of Medicine, Atlanta, GA, USA Atlanta Veterans Administration Medical Center, Decatur, GA, USA
*
*Corresponding author: Jennifer L. Gooch, Medicine/Nephrology, Emory University School of Medicine, 101 Woodruff Circle, WMB 338, Atlanta, GA 30322, USA. E-mail: jgooch@emory.edu
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Abstract

Organ transplantation is the state of the art for treating end-stage organ failure. Over 25 000 organ transplants are performed in the USA each year. Survival rates following transplantation are now approaching 90% for 1 year and 75% for 5 years. Central to this success was the introduction of drugs that suppress the immune system and prevent rejection. The most commonly used class of immunosuppressing drugs are calcineurin inhibitors (CNIs). Calcineurin is a ubiquitous enzyme that is important for T-cell function. With more people taking CNIs for longer and longer periods of time the consequences of calcineurin inhibition on other organ systems – particularly the kidney – have become a growing concern. Virtually all people who take a CNI will develop some degree of kidney toxicity and up to 10% will progress to kidney failure. In the past 15 years, research into calcineurin action has identified distinct actions of the two main isoforms of the catalytic subunit of the enzyme. The α-isoform is required for kidney function whereas the β-isoform has a predominant role in the immune system. This review will discuss the current state of knowledge about calcineurin isoforms and how these new insights may reshape post-transplant immunosuppression.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e14
Copyright
Copyright © Cambridge University Press 2012

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References

References

1Barry, J.M. and Murray, J.E. (2006) The first human renal transplants. Journal of Urology 176, 888-890CrossRefGoogle ScholarPubMed
2Schweitzer, E.J. et al. (1991) Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s. Annals of Surgery 214, 679-688CrossRefGoogle ScholarPubMed
3Murray, J., Tilney, N. and Wilson, R. (1976) Renal transplantation: a twenty-five year experience. Annals of Surgery 184, 565-573CrossRefGoogle ScholarPubMed
4Krakauer, H. et al. (1983) The recent U.S. experience in the treatment of end-stage renal disease by dialysis and transplantation. New England Journal of Medicine 308, 1558-1563CrossRefGoogle ScholarPubMed
5Administration, H.R.a.S. (2006) Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1996–2005. Healthcare Systems Bureau Division of Transplantation, Rockville, MDGoogle Scholar
6Moore, F.D. et al. (1968) Cardiac and other organ transplantation. In the setting of transplant science as a national effort. Journal of the American Medical Association 206, 2489-2500CrossRefGoogle ScholarPubMed
7Hume, D.M. et al. (1966) Comparative results of cadaver and related donor renal homografts in man, and immunologic implications of the outcome of second and paired transplants. Annals of Surgery 164, 352-397CrossRefGoogle ScholarPubMed
8Petcher, T.J., Weber, H. and Ruegger, A. (1976) Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helvetica Chimica Acta 59, 1480-1489CrossRefGoogle ScholarPubMed
9Ruegger, A. et al. (1976) Cyclosporin A, a Peptide Metabolite from Trichoderma polysporum (Link ex Pers.) Rifai, with a remarkable immunosuppressive activity. Helvetica Chimica Acta 59, 1075-1092CrossRefGoogle ScholarPubMed
10Starzl, T.E. et al. (1980) The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surgery, Gynecology and Obstetrics 151, 17-26Google ScholarPubMed
11Liu, J. et al. (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807-815CrossRefGoogle ScholarPubMed
12Schreiber, S. and Crabtree, G. (1992) The mechanism of action of cyclosporin A and FK506. Immunology Today 13, 136-142CrossRefGoogle ScholarPubMed
13Rusnak, F. and Mertz, P. (2000) Calcineurin: form and function. Physiological Reviews 80, 1483-1521CrossRefGoogle ScholarPubMed
14Luo, C. et al. (1996) Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes. Molecular and Cellular Biology 16, 3955-3966CrossRefGoogle Scholar
15Graef, I. et al. (2001) Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105, 863-875CrossRefGoogle ScholarPubMed
16Macian, F. (2005) NFAT proteins: key regulators of T-cell development and function. Nature Reviews. Immunology 5, 472-484CrossRefGoogle Scholar
17Masuda, E. et al. (1998) Signalling into the T-cell nucleus: NFAT regulation. Cellular Signalling 10, 599-611CrossRefGoogle ScholarPubMed
18Boss, V. et al. (1998) The cyclosporin A-sensitive nuclear factor of activated T cells (NFAT) proteins are expressed in vascular smooth muscle cells. Differential localization of NFAT isoforms and induction of NFAT-mediated transcription by phospholipase C-coupled cell surface receptors. Journal of Biological Chemistry 273, 19664-19671CrossRefGoogle ScholarPubMed
19Pflugl, G. et al. (1993) X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature 361, 91-94CrossRefGoogle ScholarPubMed
20Stephen, M. et al. (1989) Immunosuppressive activity, lymphocyte subset analysis, and acute toxicity of FK-506 in the rat. A comparative and combination study with cyclosporine. Transplantation 47, 60-95CrossRefGoogle Scholar
21Jordan, M.L. et al. (1991) Initial studies with FK506 in renal transplantation. Cleveland Clinic Journal of Medicine 58, 444-446CrossRefGoogle ScholarPubMed
22Guitard, J., Rostaing, L. and Kamar, N. (2011) New-onset diabetes and nephropathy after renal transplantation. Contributions to Nephrology 170, 247-255CrossRefGoogle ScholarPubMed
23Cecka, J.M. (2000) The UNOS Scientific Renal Transplant Registry – 2000. Clinical Transplantation 14, 1-18Google Scholar
24Kendrick, E. (2001) Cardiovascular disease and the renal transplant recipient. American Journal of Kidney Diseases 38(6 Suppl), S36-S43CrossRefGoogle ScholarPubMed
25Kessler, M. et al. (2006) Excess risk of cancer in renal transplant patients. Transplant International 19, 908-914CrossRefGoogle ScholarPubMed
26Tremblay, F. et al. (2002) Malignancy after renal transplantation: incidence and role of type of immunosuppression. Annals of Surgical Oncology 9, 785-788CrossRefGoogle ScholarPubMed
27Busauschina, A., Schnuelle, P. and van der Woude, F.J. (2004) Cyclosporine nephrotoxicity. Transplantation Proceedings 36(2 Suppl), 229S-233SCrossRefGoogle ScholarPubMed
28Ito, A. et al. (1989) The complete primary structure of calcineurin A, a calmodulin binding protein homologous with protein phosphatases 1 and 2A. Biochemical and Biophysical Research Communications 163, 1492-1497CrossRefGoogle ScholarPubMed
29Kuno, T. et al. (1989) Evidence for a second isoform of the catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). Biochemical and Biophysical Research Communications 165, 1352-1358CrossRefGoogle ScholarPubMed
30Kincaid, R.L. et al. (1990) Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods. Journal of Biological Chemistry 265, 11312-11319CrossRefGoogle ScholarPubMed
31Gooch, J.L. (2006) An emerging role for calcineurin Aalpha in the development and function of the kidney. American Journal of Physiology. Renal Physiology 290, F769-F776CrossRefGoogle ScholarPubMed
32Cooper, N. et al. (1985) Calmodulin-dependent protein phosphatase: immunocytochemical localization in chick retina. Journal of Cell Biology 101, 1212-1218CrossRefGoogle ScholarPubMed
33Tash, J. et al. (1988) Identification, characterization, and functional correlation of calmodulin-dependent protein phosphatase in sperm. Journal of Cell Biology 106, 1625-1633CrossRefGoogle ScholarPubMed
34Stewart, A.A. et al. (1982) Discovery of a Ca2 + - and calmodulin-dependent protein phosphatase: probable identity with calcineurin (CaM-BP80). FEBS Letters 137, 80-84CrossRefGoogle ScholarPubMed
35Fruman, D.A. et al. (1992) Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas. European Journal of Immunology 22, 2513-2517CrossRefGoogle ScholarPubMed
36Fruman, D.A. et al. (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proceedings of the National Academy of Sciences of the United States of America 89, 3686-3690CrossRefGoogle Scholar
37Perrino, B.A. et al. (2002) Substrate selectivity and sensitivity to inhibition by FK506 and cyclosporin A of calcineurin heterodimers composed of the alpha or beta catalytic subunit. European Journal of Biochemistry 269, 3540-3548CrossRefGoogle ScholarPubMed
38Fruman, D.A. et al. (1996) Measurement of calcineurin phosphatase activity in cell extracts. Methods in Enzymology 9, 146-154CrossRefGoogle ScholarPubMed
39Zhang, B.W. et al. (1996) T cell responses in calcineurin A alpha-deficient mice. Journal of Experimental Medicine 183, 413-420CrossRefGoogle ScholarPubMed
40Chan, V.S., Wong, C. and Ohashi, P.S. (2002) Calcineurin Aalpha plays an exclusive role in TCR signaling in mature but not in immature T cells. European Journal of Immunology 32, 1223-12293.0.CO;2-5>CrossRefGoogle ScholarPubMed
41Kayyali, U. et al. (1997) Cytoskeletal changes in the brains of mice lacking calcineurin A alpha. Journal of Neurochemistry 68, 1668-1678CrossRefGoogle ScholarPubMed
42Zhuo, M. et al. (1999) A selective role of calcineurin Aalpha in synaptic depotentiation in hippocampus. Proceedings of the National Academy of Sciences of the United States of America 96, 4650-4655CrossRefGoogle ScholarPubMed
43Cross, D.C. et al. (2000) Nuclear and cytoplasmic tau proteins from human nonneuronal cells share common structural and functional features with brain tau. Journal of Cellular Biochemistry 78, 305-3173.0.CO;2-W>CrossRefGoogle ScholarPubMed
44Garver, T.A. et al. (1999) Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr 181 and Thr 231. Molecular Pharmacology 55, 632-641Google Scholar
45Mandelkow, E.-M. et al. (1995) Tau domains, phosphorylation, and interactions with microtubules. Neurobiology of Aging 16, 355-363CrossRefGoogle ScholarPubMed
46Gooch, J.L. et al. (2004) Calcineurin A-alpha but not A-beta is required for normal kidney development and function. American Journal of Pathology 165, 1755-1765CrossRefGoogle ScholarPubMed
47Bueno, O.F. et al. (2002) Defective T cell development and function in calcineurin Abeta-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 99, 9398-9403CrossRefGoogle Scholar
48Bueno, O.F. et al. (2002) Impaired cardiac hypertrophic response in calcineurin Abeta-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 99, 4586-4591CrossRefGoogle ScholarPubMed
49DeWindt, L.J. et al. (2001) Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences of the United States of America 98, 3322-3327CrossRefGoogle Scholar
50Lim, H.W. et al. (2000) Reversal of cardiac hypertrophy in transgenic disase models by calcineurin inhibition. Journal of Molecular and Cellular Cardiology 32, 697-709CrossRefGoogle Scholar
51Molkentin, J. et al. (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215-228CrossRefGoogle ScholarPubMed
52Tendron, A. et al. (2003) Cyclosporin A administration during pregnancy induces a permanent nephron deficit in young rabbits. Journal of American Society of Nephrology 14, 3188-3196CrossRefGoogle ScholarPubMed
53Tendron-Franzin, A. et al. (2004) Long-term effects of in utero exposure to cyclosporin A on renal function in the rabbit. Journal of American Society of Nephrology 15, 2687-2693CrossRefGoogle ScholarPubMed
54Liu, H. et al. (2007) Developmental regulation of calcineurin isoforms in the rodent kidney: association with COX-2. American Journal of Physiology. Renal Physiology 293, F1898-F1904CrossRefGoogle ScholarPubMed
55Dinchuk, J.E. et al. (1995) Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 378, 406-409CrossRefGoogle Scholar
56Burn, S.F. et al. (2011) Calcium/NFAT signalling promotes early nephrogenesis. Developmental Biology 352, 288-298CrossRefGoogle ScholarPubMed
57Gooch, J.L. (2008) Calcineurin inhibition and development: insight from research models. Current Enzyme Inhibition 4, 29-36CrossRefGoogle Scholar
58Gooch, J.L. et al. (2007) Loss of the alpha-isoform of calcineurin is sufficient to induce nephrotoxicity and altered expression of transforming growth factor-beta. Transplantation 83, 439-447CrossRefGoogle ScholarPubMed
59Reddy, R.N. et al. (2011) Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney. Journal of Cellular and Molecular Medicine 15, 414-422CrossRefGoogle Scholar
60Pena, J.A., Losi-Sasaki, J.L. and Gooch, J.L. (2010) Loss of calcineurin Aalpha alters keratinocyte survival and differentiation. Journal of Investigative Dermatology 130, 135-140CrossRefGoogle ScholarPubMed
61Reddy, R.N. et al. (2011) Rescue of calcineurin Aalpha(-/-) mice reveals a novel role for the alpha isoform in the salivary gland. American Journal of Pathology 178, 1605-1613CrossRefGoogle ScholarPubMed
62Gooch, J.L. et al. (2001) Insulin-like growth factor-I induces renal cell hypertrophy via a calcineurin-dependent mechanism. Journal of Biological Chemistry 276, 42492-42500CrossRefGoogle Scholar
63Akool el, S. et al. (2012) Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling. Biochemical Pharmacology 83, 286-295CrossRefGoogle Scholar
64Kilka, S. et al. (2009) The proline-rich N-terminal sequence of calcineurin Abeta determines substrate binding. Biochemistry 48, 1900-1910CrossRefGoogle ScholarPubMed
65Kelly, F.M. et al. (2009) TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice. American Journal of Physiology. Renal Physiology 296, F512-F520CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Murray, J.E. (2004) Surgery of the Soul, Science History Publications, New YorkGoogle Scholar
Starzl, T. (2003) The Puzzle People: Memoirs of a Transplant Surgeon, University of Pittsburgh Press, Pittsburg, PAGoogle Scholar
Ruznak, F. and Mertz, P. (2000) Calcineurin form and function. Physiol Rev. 80, 1483–1521CrossRefGoogle Scholar
http://www.UNOS.org.Google Scholar