Pa. Craven et al., Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice, DIABETES, 50(9), 2001, pp. 2114-2125
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.