The Effects of Rapamycin in the Progression of Renal Fibrosis

• Published in: Transplantation proceedings Vol. 39; no. 2; pp. 457 - 459
• Main Authors: Damião, M.J, Bertocchi, A.P.F, Monteiro, R.M.M, Gonçalves, 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, Câmara, N.O.S
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2007; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins - genetics; Creatinine - blood; Disease Models, Animal; Disease Progression; Fibrosis - chemically induced; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunosuppressive Agents - adverse effects; Kidney - drug effects; Kidney - pathology; Kidney Failure, Chronic - pathology; Kidney Function Tests; Kidneys; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; RNA, Messenger - genetics; Sirolimus - adverse effects; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; Transforming Growth Factor beta - genetics; Urinary system involvement in other diseases. Miscellaneous; Kidney disease; Antineoplastic agent; Urinary system disease; Prognosis; Sirolimus; Renal fibrosis; Lactone; Transplantation; Macrolide; Macrocycle; Medicine; Antibiotic; Treatment; Surgery; Evolution; Graft; Protein synthesis inhibitor; Immunosuppressive agent; Antibacterial agent
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2007.01.031

Abstract 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.