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Updated: Jul 16, 2026
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
The effects of rapamycin in the progression of renal fibrosis
M J Damião1, A P F Bertocchi, R M M Monteiro
1Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo, Hospital do Rim e Hipertensão/Fundação Oswaldo Ramos, Brazil.
Unlabelled:
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)-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.
Conclusion:
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.
Insights
Rapamycin treatment reduced renal dysfunction and fibrosis in a mouse model. It initially increased TGF-beta but later reversed the TGF-beta to BMP-7 ratio, indicating a protective effect against renal fibrosis.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Renal fibrosis is a key feature of chronic kidney diseases and allograft nephropathy.
- Rapamycin possesses antiproliferative, antiviral, and antitumor properties, with potential clinical applications in chronic allograft nephropathy.
Purpose of the Study:
- To investigate the efficacy of rapamycin in mitigating renal fibrosis using a unilateral ureteral obstruction model in mice.
- To evaluate the impact of rapamycin on key fibrotic markers, transforming growth factor-beta (TGF-beta) and bone morphogenic protein-7 (BMP-7).
Main Methods:
- C57BL/6 mice underwent unilateral ureteral obstruction and were treated daily with rapamycin (0.2 mg/kg).
- Serum creatinine levels and kidney tissue expression of TGF-beta and BMP-7 mRNA were quantified via real-time PCR at multiple time points post-surgery.
Main Results:
- Rapamycin treatment significantly reduced serum creatinine levels at days 1 and 14 post-obstruction.
- Histological analysis confirmed reduced renal fibrosis in rapamycin-treated mice at day 14.
- Rapamycin initially upregulated TGF-beta but subsequently decreased its expression, while increasing BMP-7, thereby reversing the TGF-beta to BMP-7 ratio.
Conclusions:
- Rapamycin demonstrated a modest improvement in renal function and a reduction in renal fibrosis at later time points.
- The drug modulated the TGF-beta and BMP-7 expression, suggesting a protective mechanism against fibrosis development.
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