The effects of rapamycin in the progression of renal fibrosis.
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.


OBJECTIVE
Our goal was to evaluate the effect of rapamycin in an established model of renal fibrosis, unilateral ureteral obstruction.


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)-beta 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-beta 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-beta to BMP-7, allowing a more protective phenotype.


CONCLUSIONS
Rapamycin slightly ameliorated the renal dysfunction and, at later time points, induced less fibrosis and less decrease in the TGF-beta to BMP-7 ratio.
Damião
M J
MJ
Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo, Hospital do Rim e Hipertensão/Fundação Oswaldo Ramos, Brazil.
Bertocchi
A P F
AP
Monteiro
R M M
RM
Gonçalves
G M
GM
Cenedeze
M A
MA
Feitoza
C Q
CQ
Marques
G D
GD
Giannocco
G
G
Mazzali
M
M
Teixeira
V P A
VP
Dos Reis
M A
MA
Pacheco-Silva
A
A
Câmara
N O S
NO
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000139:chemically induced*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007676:Kidney Failure, Chronic / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000235:genetics
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003404:Creatinine; D020123:Sirolimus