Modulation of expression of pro- and anti-apoptotic genes during streptozotocin-induced oxidative stress in hyperglycemic mouse kidneys

Decades of intense research has shown that hyperglycemia results in the generation of reactive oxygen species, ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an efficient antioxidant counteracting system, target tissues go through a redox imbalance, leading to the activation of stress-responsive intracellular signaling pathways and major consequences of such perturbations translate into deregulated expression of cell-survival and cell-death regulating genes in vivo and in vitro. Persistent deregulation of such pathways can cause organ dysfunction, and are presumed to be responsible for the late complications of diabetes. Most studies hold hyperglycemia-induced oxidative stress 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 oxidative stress in kidneys and if so (ii) whether acute oxidative stress can influence pro- and anti-apoptotic genes and contribute to kidney-injury. Eight months old mice (female B6C3F1) were treated with STZ (dissolved in citrate buffer 100 mg/kg, ip) for six consecutive days and all the animals were sacrificed on day-7. Control animals received vehicle alone (Citrate buffer, pH 4.0). Blood and kidneys were collected for further analysis. All the STZ-exposed animals showed massive hyperglycemia (average blood glucose: Control- 120+/-10 STZ- 395.5+/-50 in mg/dl), elevated BUN concentrations (Control- 30+/-2 STZ- 121+/-11 in mg/dl), increased lipid peroxidation (Control- 8.3+/-1 STZ- 19.1+/-2 nmol/gm. protein), and DNA fragmentation (%Control- 100+/-11 STZ- 330+/-18). In contrast to these parameters, glutathione peroxidase (Enzyme level U/g. protein: Control 431+/-19 STZ- 291+/-15) and SOD activities (Control 414+/-9 STZ- 183+/-10) declined in kidney tissues. Along with the antioxidant team, expression of anti-death genes, Bcl-2 and Bcl-XL proteins decreased and mitochondria-sensitive pro-apoptotic molecular marker Cyt C level dramatically increased. In summary, this study shows that even a short-term hyperglycemia-induced oxidative stress may perturb the tissue biochemistry favorable for apoptosis and long-term impact of this may translate into serious nephrotoxic consequences.