Comparison of rapamycin with cyclosporin, and tacrolimus in regards to the development of epithelial-to-mesenchymal transition (EMT) of tubular cells and endothelial-to-mesenchymal transition (EndoMT) of peritubular capillaries (PTCs)
B. Handan Ozdemir1, F. Nurhan Ozdemir2, Alev Ok Atilgan1, Eda Akcay1, Aysegul Yucel Polat1, Aydincan Akdur3, Mehmet A. Haberal3.
1Pathology, Baskent University, Ankara, Turkey; 2Nephrology, Baskent University, Ankara, Turkey; 3Transplantation, Baskent University, Ankara, Turkey
Background: EMT of tubular cells and EndoMT of PTCs are the crucial processes in the pathogenesis of interstitial fibrosis (IF) and chronic allograft nephropathy. Rapamycin (Rp) has shown to reduce profibrotic gene expression in both experimental and clinical settings. The effects of commonly used immunosuppressives on the development of EMT and EndoMT in renal allografts are not well known. We aimed to show the influence of Rp, cyclosporin A (CsA) and tacrolimus (Tac) on the development of EMT and Endo MT in renal allografts
Methods: Of 150 patients, 53 was under Rapamycin therapy (Group R), 49 was under tacrolimus (Group T) and 48 was under CsA therapy (Group C). Interstitial leukocyte, lymphocyte, and macrophage infiltration graded. Tubular and peritubular capillary (PTC) expression of TGF-β, α-SMA, and F-actin studied to show the presence or absence of the development of EMT and Endo-MT. Follow-up biopsies analyzed for the development of diffuse interstitial fibrosis (IF).
Results: The expression of tubular α-SMA and F-actin, therefore, the development of EMT and the tubular TGF-β expression found to be lowest in Group R and highest in Group C compared to Group T (p<0.001). PTC α-SMA and F-actin expression, therefore, the development of Endo-MT, and PTC TGF-β expression, also found lowest in Group R compared to Group C and T (p<0.01). Group T showed the highest Endo-MT and PTC TGF-β expression compared to Group C and Rp. The degree of inflammation, lymphocyte, and macrophage infiltration and the development of IF showed a significant correlation with both PTC and tubular α-SMA, F-actin, and TGF-β expression (p<0.001). The incidence of the development of IF was found lowest in Group R compared to other Groups (p<0.001). The development of IF during 18 months after study biopsy was 1,9 %, 35.4%, and 57% for Group R, Group C, and Group T, respectively. The development of EMT and Endo-MT showed a significant negative correlation with graft survival (p<0.001).
Conclusion: Our findings clarified that Rp showed an inhibitory effect on the development of EMT and EndoMT in renal allografts compared to CsA and Tac. As a result, less IF observed in recipients under Rp therapy and excellent graft survival found in patients where IF was prevented.
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