The potential role of mesenchymal stem cells enhanced with melatonin in renal damage induced experimentally by cecal ligation and puncture in rats.

Abstract

INTRODUCTION: Sepsis-induced acute kidney injury (AKI) carries high mortality, and treatment options beyond supportive care are limited. Mesenchymal stem cells (MSCs) offer therapeutic potential due to their paracrine properties but are limited by poor survival and engraftment post-transplantation. Preconditioning with melatonin (MEL) may enhance MSC efficacy. This study aimed to compare the renoprotective effects of MSCs alone versus melatonin-preconditioned MSCs (MSCs+MEL) in a rat model of septic AKI. METHODS: Polymicrobial sepsis was induced in male Wistar rats via cecal ligation and puncture (CLP). Three hours post-CLP, animals received an intraperitoneal injection of either MSCs (1 × 10^6), MSCs+MEL, or vehicle. Renal function, oxidative/antioxidant markers, inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB), apoptosis, and histopathology were assessed. RESULTS: CLP-induced sepsis resulted in significant AKI, evidenced by elevated inflammatory and apoptotic markers, oxidative stress, and histopathological damage. Both treatment groups showed improved kidney function and histology compared to untreated septic controls. However, the MSCs+MEL combination was significantly more effective. It superiorly reduced the expression of IL-1β, IL-6, TNF-α, NF-κB, attenuated oxidative stress and apoptosis, enhanced antioxidant defenses, and resulted in more pronounced histological improvement, as confirmed by immunohistochemistry. DISCUSSION: Preconditioning with melatonin synergistically enhances the therapeutic efficacy of MSCs in septic AKI. The MSCs+MEL combination exerts superior renoprotection by more robustly mitigating inflammation, oxidative stress, and apoptosis while promoting tissue repair.