Renal ischemia is a common cause of acute kidney injury (AKI), particularly in critical care settings, and remains a major challenge in nephrology due to the lack of effective therapeutic options. In AKI, there is an overstimulation of NAD⁺-consuming enzymes leading to NAD⁺ depletion. To help replenish cellular NAD⁺ stores, this study explores for the first time the therapeutic potential of activating nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD⁺ salvage pathway, in a rat model of unilateral renal ischemia-reperfusion injury (IRI). Our findings demonstrate that SBI797812 (SBI)-induced NAMPT activation significantly improves renal function post-IRI, primarily through the NAD⁺/SIRT1/PGC-1α signaling pathway. NAMPT activation resulted in significant improvement in kidney function, including restored urine flow rate, reduced creatinine and blood urea nitrogen (BUN) levels, and decreased kidney injury biomarkers such as KIM-1 and NGAL. Additionally, SBI led to a reduction in inflammatory markers (NFκB, TNF-α and IL-6), oxidative stress markers, and caspase-3, indicating enhanced renal protection. Western blot analysis further revealed upregulation of key mitochondrial biogenesis markers, including SIRT1, PGC-1α, and TFAM, highlighting the link between NAD⁺ restoration and improved mitochondrial function. In contrast, the inhibition of NAMPT with FK866 exacerbates injury, as indicated by worsened histological features, increased inflammation, and tubular necrosis, confirming the crucial role of NAMPT in mitigating ischemic damage. Considering the importance of NAD metabolism in mitochondrial function and cellular resiliency to tissue injury, these results underscore NAMPT activation as a promising therapeutic strategy for renal IRI, offering new insights for the management of ischemic AKI.

Preconditioned mesenchymal stem cells (MSCs) represent an advanced method to overcome the challenges related to their survival rate, differentiation, and activity maintenance. L-carnitine has demonstrated antioxidant and anti-apoptotic effects on injured cardiac cells. However, limited research has been conducted to explore their combined effect on cardiac tissue injury. Therefore, the present study aimed to conduct a comparative and comprehensive study investigating the role of L-carnitine-pre-treatment on the immunomodulation of inflammation, apoptosis, and differentiation of MSCs and their impact on cardiac toxicity induced by Doxorubicin (DOX). Rats were divided into group I (control), group II (DOX), group III (DOX+MSCs), group IV (DOX+L-carnitine), group V (DOX+L-carnitine pre-treated MSCs). CK-MB, troponin I, MDA, and catalase levels were improved in the treated groups (III, IV, and V). The degeneration and necrosis of the cardiomyocytes were reduced in the treated groups. They regained their normal architecture in the L-carnitine pre-treated MSCs group. These findings were augmented by analyzing the immunomodulators; NF-ҡβ, TNFα, and IL-1β, the proliferative indicators Ki-67, and hsp90, the cardiac differentiation marker TH and the apoptotic regulators; caspase 3 and Bcl2. These results demonstrate the optimal regenerative and therapeutic effects of L-carnitine pre-treated MSCs representing an efficient tool for future stem cell therapy.