Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice

Ex vivo and in vitro observations implicate super-oxide as a mediator of ce ll injury in diabetes, but in vivo evidence is lacking. In the current stud ies, parameters of glomerular injury were examined in hemizygous nondiabeti c transgenic mice (SOD) and streptozotocin-diabetic (D) transgenic mice (D- SOD), which overexpress human cytoplasmic Cu2+/Zn2+ superoxide dismutase (S OD-1), and in corresponding wild-type littermates (WT, D-WT) after 4 months of diabetes. In both SOD and D-SOD mice, renal cortical SOD-1 activity was twofold higher than values in the WT mice; blood glucose and glycosylated hemoglobin (GHb) levels did not differ in the two diabetic groups. Urinary albumin excretion, fractional albumin clearance, Urinary transforming growt h factor-beta (TGF-beta) excretion, glomerular volume, glomerular content o f immunoreactive TGF-beta, and collagen alpha1. (IV) and renal cortical mal ondialdehyde (MDA) levels were significantly higher in D-WT mice compared w ith corresponding values in D-SOD mice. Glomerular volume, glomerular conte nt of TGF-beta and collagen TV, renal cortical MDA, and urinary excretion o f TGF-beta in D-SOD mice did not differ significantly from corresponding va lues in either the nondiabetic SOD or WT mice. In separate groups of mice s tudied after 8 months of diabetes, mesangial matrix area, calculated as a f raction of total glomerular tuft area, and plasma creatinine were significa ntly higher in D-WT but not in D-SOD mice, compared with corresponding valu es in the nondiabetic mice. In vitro infection of mesangial cells (MC) with a recombinant adenovirus encoding human SOD-1 increased SOD-1 activity thr eefold over control ce. [Is and prevented the reduction of aconitase activi ty, an index of cellular superoxide, and the increase in collagen synthesis that otherwise occurred in control MC in response to culture with 300 or 5 00 mg/dl glucose. Thus, increases in cellular SOD-1 activity attenuate diab etic renal injury in vivo and also prevent stimulation of MC matrix protein synthesis induced in vitro by high glucose.