Decades of intense research has shown that hyperglycemiainduced ROS production can lead to a redox-imbalance causing oxidative stress (OS) in a variety of target organs in vivo. In the absence of an efficient antioxidant counteracting system, massive OS often leads to activation of stress-responsive signaling pathways resulting in deregulated expression of pro-survival and/or pro-death genes. Persistent deregulation of such pathways eventually masterminds late complications of diabetes. Most studies hold hyperglycemia-induced OS as the ‘cause’, and premature onset of apoptosis as the ‘effect’. This ‘cause and effect’ axis ultimately initiates the development and progression of macro and microvascular complications including diabetic nephropathy. This acute in vivo study was designed to investigate: (i) whether streptozotocin (STZ)-induced hyperglycemia can cause OS in kidneys; and if so (ii) whether acute OS can influence anti-apoptotic genes and Cyt c release, and contribute to kidney-injury. Mice (8 mo old; ♀B6C3F1) were treated with STZ (dissolved in citrate buffer pH 4.0; 100 mg/kg, ip) for six consecutive days and all the animals were sacrificed on day-7. Control animals received vehicle alone (Citrate buffer). Blood and kidneys were collected for tissue biochemistry and pathology. All the STZ-exposed animals showed massive hyperglycemia (average blood glucose in mg/dl: Cont- 120±10; STZ- 395.5±50), elevated BUN (in mg/dl: Cont- 30±2; STZ121±11), increased lipid peroxidation (nmol/gm. Protein: Cont8.3±1; STZ- 19.1±2), increased DNA fragmentation (%Control100±11; STZ-330±18), and presence of apoptotic nuclei were found scattered throughout the tissues. In contrast, glutathione peroxidase (U/gm. protein: Cont 431±19; STZ- 291±15) and SOD activity (Cont 414±9; STZ- 183±10) declined in kidneys. Along with the antioxidant team, expression of anti-death Bcl-2 and BclXL proteins decreased and Cyt c (cytosolic) release dramatically increased. In summary, this study showed that even a short-term hyperglycemia-induced OS may perturb the tissue biochemistry favorable for apoptosis and long-term impact of this may translate into serious nephrotoxic complications.