The mTOR inhibitor Rapamycin protects from premature cellular senescence early after experimental kidney...

Area of Science:

• Nephrology
• Immunology
• Cellular Biology

Background:

• Interstitial fibrosis and tubular atrophy (IFTA) are primary causes of kidney allograft dysfunction.
• Premature cellular senescence is implicated in IFTA development.
• Rapamycin, an mTOR inhibitor, shows anti-senescence effects in models but raises concerns due to antiproliferative effects post-transplant.

Purpose of the Study:

• To investigate the effect of low-dose Rapamycin on cellular senescence in a rat kidney transplantation model.
• To assess Rapamycin's impact on senescence-associated secretory phenotype and immune cell infiltration.
• To evaluate Rapamycin's effects on graft function, structure, and host physiology.

Main Methods:

• A rat kidney transplantation model was used.
• Rapamycin was administered at a loading dose of 3 mg/kg and a daily maintenance dose of 1.5 mg/kg for 7 days.
• Senescence markers (p16INK4a), proinflammatory cytokines (MCP-1, IL-1β, TNF-α), immune cell infiltration, and graft function were assessed.

Main Results:

• Low Rapamycin trough levels (2.1-6.8 ng/mL) effectively prevented p16INK4a-positive cell accumulation in tubules, interstitium, and glomeruli.
• Expression of senescence-associated secretory phenotype cytokines was abrogated.
• Monocyte/macrophage and CD8+ T-lymphocyte infiltration decreased, and tubular function was preserved.
• No impairment in structural recovery, elevated glucose levels, or weight loss was observed.

Conclusions:

• Low-dose Rapamycin in the early post-transplant period inhibits premature cellular senescence in kidney allografts.
• This intervention protects against senescence-associated inflammation and immune cell infiltration.
• Rapamycin treatment preserved graft function and structure without adverse systemic effects, suggesting a potential strategy to prevent IFTA.