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

Abstract

Interstitial fibrosis and tubular atrophy, a major cause of kidney allograft dysfunction, has been linked to premature cellular senescence. The mTOR inhibitor Rapamycin protects from senescence in experimental models, but its antiproliferative properties have raised concern early after transplantation particularly at higher doses. Its effect on senescence has not been studied in kidney transplantation, yet. Rapamycin was applied to a rat kidney transplantation model (3 mg/kg bodyweight loading dose, 1.5 mg/kg bodyweight daily dose) for 7 days. Low Rapamycin trough levels (2.1–6.8 ng/mL) prevented the accumulation of p16INK4a positive cells in tubules, interstitium, and glomerula. Expression of the cytokines MCP-1, IL-1β, and TNF-α, defining the proinflammatory senescence-associated secretory phenotype, was abrogated. Infiltration with monocytes/macrophages and CD8+ T-lymphocytes was reduced and tubular function was preserved by Rapamycin. Inhibition of mTOR was not associated with impaired structural recovery, higher glucose levels, or weight loss. mTOR inhibition with low-dose Rapamycin in the immediate posttransplant period protected from premature cellular senescence without negative effects on structural and functional recovery from preservation/reperfusion damage, glucose homeostasis, and growth in a rat kidney transplantation model. Reduced senescence might maintain the renal regenerative capacity rendering resilience to future injuries resulting in protection from interstitial fibrosis and tubular atrophy.

COVID-19 Infection and Response to Vaccination in Chronic Kidney Disease and Renal Transplantation: A Brief Presentation

“…There are, however, situations not widely recognizable (e.g., enhanced senescence of the graft followed by tubular atrophy and interstitial fibrosis) that lead to chronic allograft dysfunction. Experimental studies have shown that inhibition of inflammatory infiltration by macrophages and CD8+ lymphocytes and reduction in proinflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1), IL-1b, and TNF-a, with the use of mammalian/mechanistic target of rapamycin (mTOR) inhibitors, may prevent the emergence of phenotypic changes linked to senescence and chronic graft dysfunction [64].…”

mTOR Inhibitor Rapalink-1 Prevents Ethanol-Induced Senescence in Endothelial Cells

“…Taken together, these findings suggest that Rapalink-1, by inhibiting the activation of NF-kB, P38, ERK, and 4EBP1, alleviated Lamin B1 expression and suppressed the expression of P21. Previous studies have shown that blocking the activation of NF-κB, MAPKs, and mTOR can dampen senescence in various cell types in vivo and in vitro [17][18][19]. The accumulation of senescent cells has been observed in atherosclerotic lesions [6,7,13].…”

“…The expression of SASP factors is regulated by MAPKs and mediated through NF-kB transcriptional activity [14]. Blocking NF-κB, MAPKs, and mTOR could inhibit cellular senescence and SASP and increase life span [15][16][17][18][19]. Moreover, activation of these pathways has been implicated in cardiovascular diseases, including atherosclerosis and IAs [15,[20][21][22][23].…”

Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies

“…By inhibiting the mTOR pathway, rapamycin may modulate these cellular processes and even reduce the appearance of new senescent cells by promoting homeostasis via the removal of dysfunctional proteins and aged organelles through autophagy. Rapamycin has also been shown to reduce the SASP [67][68][69] to inhibit the production of pro-inflammatory molecules and their signaling pathways. Through an mTOR-dependent reduction in NF-κB transcriptional activity, rapamycin can inhibit the translation of inflammatory SASP factors [40].…”