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Diabetic nephropathy (DN) is a significant complication of diabetes mellitus (DM) and a primary driving force for renal failure. The development of DN is influenced by immunological dysregulation, and chronic inflammation. Despite the promise of mesenchymal stromal cell-conditioned media (MSCs-CM) as a beneficial intervention for various diseases, its clinical application is hindered by insufficient studies and a limited understanding of the underlying mechanisms. This study examines the beneficial effects and potential mechanisms through which MSCs-CM attenuates early diabetic renal injury in a streptozotocin (STZ)-induced diabetic rat model, targeting oxidative stress-induced inflammation response, and renal damage triggered by hyperglycemia, via compare the therapeutic impact and associated anti-inflammatory modulatory profiles of intravenous versus pancreatic-targeted MSCs-CM delivery in STZ-induced early diabetic renal injury. Forty male Wistar rats were randomly allocated to five groups (n = 8/group) including: Control, DN (rats that had fasted overnight, 50 mg/kg b.wt. STZ was dissolved in cold citrate buffer (pH 4.5) and administered intraperitoneally fifteen minutes after 110 mg/kg b.wt. of nicotinamide (NA) prepared in normal physiological saline and injected intraperitoneally), DN+ Amaryl (800 µg/kg body weight per day), DN+ intravenous MSCs-CM (0.5 mL MSCs-CM was given intravenously (IV) through the tail vein) & DN+ pancreatic MSCs-CM (0.5 mL MSCs-CM was locally administered going straight into the pancreas). All treatments continued for 28 days. The treatment regimens led to a significant decline in serum insulin, HbA1c, and blood glucose levels. Additionally, the treatments reduced oxidative stress and increased antioxidant enzyme activities/concentrations, as demonstrated by the kidney's decreased lipid peroxidation marker (MDA), NO as a marker of nitric oxide/oxidative-nitrosative stress and elevated antioxidant markers (catalase, superoxide dismutase, and glutathione). The inflammatory mediator NF-κB, COX-2, and iNOS expression were significantly reduced by MSCs-CM in conjunction with the significant decrease in IL-1β, PGE2, TNF-α, and IL-6. These findings suggest that infusing MSCs-CM into T1DM rat model support further investigation of MSCs-CM as a potential therapeutic approach.