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

Amina F. Hussein¹Manal Elkhadragy²Rasha S. Elbeltagy¹Ahmed Esmat Abdel Moneim^1*Mohga S. Abdalla¹

• ¹Helwan University, Helwan, Egypt
• ²Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia

Sepsis has become a major health concern in severely ill patients. It is a significant risk factor for shock and multiple organ failure. One of the most common side effects of sepsis that predicts a high burden of death and morbidity is acute kidney injury (AKI). Despite advancements in understanding its pathophysiology, therapeutic choices are still limited to dialysis and renal transplantation. Considering the antiapoptotic, immunomodulatory, antioxidative, and pro-angiogenic effects of mesenchymal stem cells (MSCs), they may be a promising candidate for kidney injury management. The low engraftment, impaired paracrine ability, and delayed administration of MSCs are the main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies, like melatonin (MEL), to improve MSCs survival rates and paracrine ability. This study investigated the efficacy of intraperitoneally injected MSCs alone and MEL + MSCs on sepsis-induced kidney injury in rats. This study aims to investigate the protective effect of stem cells alone and stem cells enhanced with melatonin against inflammation and oxidative stress caused by induced sepsis in animals. Male Wistar albino rats received cecal ligation and puncture (CLP) surgery under anesthesia to induce polymicrobial sepsis. MSCs (1 × 10^6) and MSCs + MEL were intraperitoneally (i.p.) injected 3 h after CLP. Kidney functions, oxidative and antioxidative markers, inflammatory markers, and apoptotic markers were measured. Septic rats exhibited elevation of inflammatory and apoptotic markers along with biochemical parameters and histological abnormalities. Both MSCs and MSCs + MEL-treated groups achieved an enhancement of kidney function, which was confirmed by histopathological examination. Also, there was a reduction in gene expression levels of IL-1β, IL-6, and TNF-α. The results emphasize that combined therapy with MSCs + MEL relieved the inflammation witnessed by decreasing IL-1β, TNF-α, and NF-κB levels in the sepsis group. Noticeable improvement in histopathological examinations and immunohistochemistry analysis of NF-κB and TNF-α were found in MSC + MEL-treated animals, which proves earlier studies. The combined treatment (MSCs + MEL) exhibited superior renoprotective effects compared to MSCs alone, significantly reducing oxidative stress, inflammation, and apoptosis while enhancing antioxidant defenses and promoting tissue repair.