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.

Background/Objectives: Using a well-established model of streptozotocin-induced diabetic retinopathy (DR), this study sought to evaluate the neuroprotective effect of intravitreal Forskolin (FSK) on retinal ganglion cell survival and glial activation and explore the association of circulating miR-200b with metabolic and oxidative stress in DR. Methods: A total of 18 male Wistar rats were divided into a control group (n = 6) and a streptozotocin-induced diabetic group (n = 12), which were further divided into diabetic control and FSK-treated groups (n = 6 each). Total antioxidant capacity (TAC), total peroxide (TP), triglycerides (TGs), total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured. qRT-PCR analysis for miRNA-200b and immunohistochemistry were performed. Results: Diabetic rats showed oxidative stress and hyperlipidemia associated with increased circulating miR-200b levels. The retina showed reduced neuron numbers (Caspase-3), altered glial and astrocyte staining (IBA1, GFAP), and changes in microglia/macrophage morphology and distribution. Intravitreal FSK improved retinal ganglion cell survival and reduced glial activation, while systemic lipid profile and oxidative stress markers remained largely unchanged. Circulating miR-200b levels showed a positive correlation with oxidative stress markers across groups. Conclusions: Intravitreal FSK was able to limit the disease exacerbation via improved neuronal survival through inhibition of apoptosis. FSK did not produce observable qualitative changes in GFAP expression or IBA1+ cell morphology under the conditions tested.