Artículos de revistas
The Effects Of Rapamycin In The Progression Of Renal Fibrosis
Registro en:
Transplantation Proceedings. , v. 39, n. 2, p. 457 - 459, 2007.
411345
10.1016/j.transproceed.2007.01.031
2-s2.0-33947128718
Autor
Damiao M.J.
Bertocchi A.P.F.
Monteiro R.M.M.
Goncalves G.M.
Cenedeze M.A.
Feitoza C.Q.
Marques G.D.
Giannocco G.
Mazzali M.
Teixeira V.P.A.
dos Reis M.A.
Pacheco-Silva A.
Camara N.O.S.
Institución
Resumen
Renal fibrosis is a hallmark of end-stage renal diseases and of chronic allograft nephropathy (CAN). Rapamycin, besides its action through blockade of lymphocyte proliferation, also has antiproliferative, antiviral, and antitumor actions. Its use in clinical in patients with CAN has recently been advocated. Objectives: Our goal was to evaluate the effect of rapamycin in an established model of renal fibrosis, unilateral ureteral obstruction. Materials and Methods: C57BL/6 mice were divided into two groups, treated or not with daily doses of rapamycin (0.2 mg/kg) beginning on day-1. The obstruction was performed as day 0. Blood and kidney tissues were collected at 1, 4, 7, and 14 days after the surgery to quantify bone morphogenic protein (BMP)-7 and transforming growth factor (TGF)-β mRNA by real time PCR. Results: Daily treatment with rapamycin caused a significant reduction in serum creatinine at day 1 (0.57 ± 0.03 vs 0.95 ± 0.15 mg/dL, P = .002) and at day 14 (0.56 ± 0.04 vs 0.73 ± 0.07 mg/dL, P = .040). This profile was corroborated by histological morphometric analyses showing less fibrosis at day 14. However, rapamycin surprisingly induced an upregulation of TGF-β at day 4 (3.05 ± 0.46 vs 1.85 ± 0.41, P = .006) and at day 7 (6.33 ± 0.55 vs 4.97 ± 0.38, P = .024) with a reduced expression by day 14 (4.03 ± 1.07 vs 7.89 ± 0.83, P < .001). Surprisingly, rapamycin also promoted an increment in BMP-7, completely reversing the ratio of TGF-β to BMP-7, allowing a more protective phenotype. Conclusion: Rapamycin slightly ameliorated the renal dysfunction and, at later time points, induced less fibrosis and less decrease in the TGF-β to BMP-7 ratio. © 2007 Elsevier Inc. All rights reserved. 39 2 457 459 Wolfe, R.A., Ashby, V.B., Milford, E.L., Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant (1999) N Engl J Med, 341, p. 1725 Hariharan, S., Johnson, C.P., Bresnahan, B.A., Improved graft survival after renal transplantation in the United States, 1988 to 1996 (2000) N Engl J Med, 342, p. 605 Halloran, P.F., Melk, A., Barth, C., Rethinking chronic allograft nephropathy: the concept of accelerated senescence (1999) J Am Soc Nephrol, 10, p. 167 Zeisberg, M., Hanai, J., Sugimoto, H., BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury (2003) Nat Med, 97, p. 964 Yang, J., Dai, C., Liu, Y., A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition (2005) J Am Soc Nephrol, 161, p. 68 Okada, H., Kalluri, R., Recapitulation of kidney development paradigms by BMP-7 reverses chronic renal injury (2005) Clin Exp Nephrol, 92, p. 100 Stallone, G., Schena, A., Infante, B., Sirolimus for Kaposi's sarcoma in renal-transplant recipients (2005) N Engl J Med, 35213, p. 1317 Lee, V.W., Chapman, J.R., Sirolimus: its role in nephrology (2005) Nephrology (Carlton), 106, p. 606 Morales, J.M., Immunosuppressive treatment and progression of histologic lesions in kidney allografts (2005) Kidney Int, 99 (SUPPL), pp. S124 Bumbea, V., Kamar, N., Ribes, D., Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus (2005) Nephrol Dial Transplant, 2011, p. 2517 Shihab, F.S., Bennett, W.M., Yi, H., Sirolimus increases transforming growth factor-beta1 expression and potentiates chronic cyclosporine nephrotoxicity (2004) Kidney Int, 654, p. 1262 Song, K., Wang, H., Krebs, T.L., Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation (2006) EMBO J, 251, p. 58 van der Poel, H.G., Hanrahan, C., Zhong, H., Rapamycin induces Smad activity in prostate cancer cell lines (2003) Urol Res, 306, p. 380