© Borgis - Postępy Nauk Medycznych 2/2014, s. 114-117
*Robert Świder, Magdalena Durlik, Agnieszka Perkowska
Przemiana nabłonkowo-mezenchymalna w kontekście przewlekłego włóknienia i czynności przeszczepionych nerek
Epithelial-mesenchymal transition in the context of chronic fibrosis and function of kidney transplants
Department of Transplantation Medicine and Nephrology, Prof. Tadeusz Orłowski Transplantation Institute, Warsaw Medical University
Head of Department: prof. Magdalena Durlik, MD, PhD
Streszczenie
Główną przyczyną późnej niewydolności nerek po przeszczepie jest włóknienie ich zrębu i zanik cewek nerkowych. Identyfikowanie wszelkich możliwych przyczyn IF/TA (ang. interstitial fibrosis/tubular athrophy) oraz doskonalenie metod specyficznego leczenia takich przypadków, to kwestie, które w przyszłości będą stać przed transplantologią nerek. W prasie fachowej pojawiają się dowody sugerujące, że przemiana nabłonkowo-mezenchymalna (EMT) jest ważnym wydarzeniem w uszkodzeniu własnych i przeszczepionych nerek łącznie z włóknieniem zrębu/zanikiem cewek nerkowych. Podczas przemiany nabłonkowo-mezenchymalnej (EMT) komórki cewek nerkowych ulegają przekształceniu w miofibroblasty przez stopniowy proces przemiany.
W prezentowanym artykule, o charakterze przeglądowym, rozpatrywane są molekularne i komórkowe szlaki przemiany nabłonkowo-mezenchymalnej (EMT) oraz rola, jaką pełnią w progresji przewlekłego włónienia przeszczepionej nerki. Potencjalne możliwości terapeutyczne dotyczące przemiany nabłonko-mezenchymalnej nadal pozostają kwestią do dyskusji, jednak wiele faktów przemawia za tym, że EMT odgrywa główną w patogenezie przewlekłego włóknienia zrębu i zaniku cewek nerkowych (IF/TA), a w konsekwencji do przewlekłej dysfunkcji przeszczepu (ang. chronic allograft dysfunction, CAD). Wielkość udziału EMT w włóknieniu przeszczepu nerki pozostaje nierozpoznana. Wiele danych jest branych pod uwagę w celu określenia, czy przemiana nabłonkowo-mezenchymalna może być użytecznym markerem w ocenie progresji przewlekłej niewydolności przeszczepionych nerek.
Summary
The principal cause of delayed renal failure after transplantation is interstitial fibrosis and tubular atrophy (IF/TA). Identification of all possible causes of IF/TA and improvement of the methods of specific treatment of such cases will be important issues for renal transplantation medicine in the future. Evidence to suggest that the epithelial-mesenchymal transition (EMT), alongside IF/TA, is a significant event in the process of damaging the patient’s own and transplanted kidneys has recently been appearing in the professional literature. In the course of the EMT, renal tubular cells undergo a process of gradual transformation into myofibroblasts.
The presented review article discusses the molecular and cellular pathways of the EMT and the role they play in the progression of chronic fibrosis of the kidney transplant. The potential therapeutic options for the EMT are still a subject for discussion but many facts suggest that the EMT plays the principal role in the pathogenesis of chronic interstitial fibrosis and tubular atrophy (IF/TA), and as a consequence of chronic allograft dysfunction (CAD). The importance of the EMT involvement in kidney transplant fibrosis has not been elucidated. Many data are taken into account for the purpose of determining whether the EMT can be a useful marker in the assessment of chronic allograft dysfunction progression.
Introduction
Interstitial fibrosis/tubular atrophy in kidney transplants is one of the principal causes of delayed dysfunction. IF/TA is a chronic progressive non-specific histopathologically irreversible nosocomial entity with an early onset after transplantation, associated with significantly increased morbidity and mortality of the allograft recipients. A new approach aimed at obtaining longer vitality of kidney transplants is identification of the IF/TA causes and development of a strategy of specific treatment of such cases. Interstitial fibroblasts are the main source of renal fibrosis. Under the effect of “stress”, renal interstitial fibroblasts divide and spread, producing profibrotic molecules. More than 1/3 of the fibroblasts associated with renal fibrosis originate from renal tubular epitheliums, from the sites where a damaging factor was active as a result of the EMT. In the course of the EMT, renal tubular cells are gradually transformed into myofibroblasts, which includes the loss of links between tubular cells, the loss of E-cadherin expression, de novo expression of smooth muscle α-actin, reorganisation of actins, abnormalities of the tubular basement membrane ultrastructure, and migration and invasion of fibroblast cells producing basic profibrotic molecules for the fibrosis process such as collagen type I and III and fibronectin.
Prolonged action of the factors damaging the kidney transplant is undoubtedly the main cause of chronic allograft dysfunction and consequential kidney transplant loss. Prolonged IF/TA and damage to renal blood vessels and glomeruli make kidney transplants lose their function over variable periods of time (several months to several or more than ten years after transplantation). The above-described situation is defined as chronic allograft dysfunction in the professional literature; it makes any further therapeutic options very limited (1). The incidence of chronic allograft dysfunction ranges from 23% at five years after transplantation to 60% at ten years after transplantation. It is necessary to effectively counteract this phenomenon, because loss of the transplanted organs not only deteriorates patients’ health but also increases the number of patients awaiting transplantation (2).
Characteristics of epithelial-mesenchymal transition
The epithelial-mesenchymal transition is a biological process that enables polarised cells of the renal tubular epithelium, which normally interact between the basement membrane and their own parabasal surface, to obtain phenotypic characteristics of a mesenchymal cell: increased migration ability, invasiveness, increased resistance to apoptosis, and markedly increased production of extracellular matrix (ECM) constituents. The end of the epithelial-mesenchymal transition is signalled by damage to the basement membrane and formation of a mesenchymal cell which obtains ability to migrate from the monolayer renal tubular epithelium from which it originates to the renal interstitium. Numerous molecular processes participate in EMT initiation and make its completion possible. They include activation of transcription factors, expression of specific surface proteins, reorganisation and expression of cytoskeleton proteins, production of enzymes breaking down extracellular matrix, and changes in genetic information expression. In many cases, the above-listed factors are used as biomarkers for confirmation of the completed epithelial-mesenchymal transition process of the tubular epithelial cells (3-5).
The groundbreaking study of Elizabeth Hay, who was the first to describe the process of “epithelial-mesenchymal transformation”, was based on an animal model (notochord formation in chick embryos). Shortly after, the term “transformation” was replaced by “transition”, reflecting partial reversibility of the process, which is in fact a separate form of neoplastic transformation (5, 6). Phenotypic plasticity of the EMT is manifested through a reverse process of mesenchymal-epithelial transition (MET) which engages a change of the mesenchymal cell phenotype to epithelial derivatives (7, 8).
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Piśmiennictwo
1. Seron D: Interstitial fibrosis and tubular atrophy in renal allograft protocol biopsies as a surrogate of graft survival. Transplantation Proceedings 2009; 41: 769-770.
2. Bedi S, Vidyasagar A, Djamaki A: Epithelial to mesenchymal transition and chronic allograft tubuloitestitial fibrosis. Transplant Reviews 2008; 22(1): 1-5.
3. Jevnikar AM, Mannon RB: Late kidney allograft loss: what we know about it, and what we can do about it. Clinical Journal of American Society of Nephrology 2008; 3: 56-67.
4. Carew RM, Wang B, Kantharidis Ph: The role of EMT in renal fibrosis. Cell Tissue Research 2012; 347: 103-116.
5. Kalluri R, Weinberg RA: The basics of epithelia-mesenchymal transition. Journal of Clinical Investigation 2009; 199(6): 1420-1428.
6. Fragiadaki M, Mason MR: Epithelial-mesenchymal transition in renal fibrosis – evidence for against. International Journal of Experimentl Pathology 2011; 92: 143-150.
7. Zeisberg M, Kalluri R: The role of epithelial-to-mesenchymal transition in renal fibrosis. Journal of Molecular Medicine 2004; 82: 175-181.
8. Kalluri R, EMT: When epithelial cells decide to become mesenchymal-like cells. The Journal of Clinical Investigation 2009; 119: 1417-1419.
9. Hertig A, Verine J, Mougenot B et al.: Risk factors for early epithelial to mesenchymal transition in renal grafts. American Journal of Transplantation 2006; 6: 2937-2946.
10. Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of Clinical Investigation 2003; 112: 1776-1784.
11. Del Prete D, Ceol M, Anglani F et al.: Early activation of fibrogenesis in transplanted kidneys: a study on serial renal biopsies. Experimental and Molecular Pathology 2009; 87: 141-145.
12. Rastaldi MP, Ferrario F, Giardino L et al.: Epithelial-mesenchymal transition of tubular epithelia cells in human renal biopsies. Kidney International 2002; 62: 137-146.
13. Le Hir M, Hegyi CI, Cueni-Loffing D et al.: Characterization of renal interstitial fibroblast-specific protein 1/S100A4 – positive cell in healthy and inflamed rodent kidneys. Histochemical Cell Biology 2005; 123: 335-348.
14. Birk PE: Surveillance biopsies in children post-kidney transplant. Pediatrician Nephrology 2012; 27: 753-760.
15. Hertig A, Flier SN, Kalluri R: Contribution of epithelial plasticity to renal transplantation – associated fibrosis. Transplantation Proceedings 2010; 42: 7-12.
16. Ishikawa A, Tanaka M, Ohta N et al.: Prevention of interstitial fibrosis of renal allograft by angiotensin II blockade. Transplantation Proceedings 2006; 38: 3498-3501.
17. Yokoyoma T, Konno O, Nakamura Y et al.: Interstitial fibrosis and tubular atrophy on protocol biopsies at 1 year after renal transplantation. Transplantation Proceedings 2012; 44: 607-609.
18. Barbari A, Stephan A, Masri AM et al.: Chronic graft dysfunction; donor factors. Transplantation Proceedings 2001; 33: 2695-2698.
19. Mannon RB, Matas AJ, Grande J et al.: Inflammation in areas of tubular atrophy in kidney allograft biopsies: a potent predictor of allograft failure. American Journal of Transplantology 2010; 10: 2066-2073.
20. Lopez-Hernandez FJ, Lopez-Novoa JM: Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Research 2012; 347: 141-154.
21. Tyler JR, Robertson H, Booth TA et al.: Chronic allograft nephropathy: intraepithelial signals generated by transforming growth factor-b and bone morphogenetic protein-7. American Journal of Transplantology 2006; 6: 1367-1376.
22. Nankivell BJ, Borrows RJ, Chir MB et al.: The natural history of chronic allograft nephropathy. The New England Journal of Medicine 2003; 11: 2326-2333.
23. Martin L, Guilbeau C, Bocrie O et al.: Expression of TGFβ-1 and type i TGFβ-receptor on sequential biopsies of renal transplant with chronic allograft nephropathy. Transplatation Proccedings 2006; 38: 2327-2329.
