Increased endogenous antioxidants and reduced basement membrane thickening in Ames dwarf mouse kidney

Abstract

Experimental evidence suggests that disease- and age-related thickening of glomerular (GBM) and tubular (TBM) basement membranes may be related to increases in reactive oxygen species (ROS). Studies also suggest that antioxidants may function as renoprotectants against such ROS-induced damage. The current study focuses on metallothionein (MT) and glutathione (GSH), both of which exhibit potent antioxidant functions. Ames dwarf mice, which exhibit elevated tissue antioxidant levels (catalase, Cu/Zn superoxide dismutase, GSH) and an average life span significantly greater (50–65%) than wild type controls, were used to test our hypothesis that increased levels of renal MT and GSH are concomitant with decreased rates of renal basement membrane thickening. A competitive ELISA assay was developed to quantitate both endogenously polymerized and “total” (glutaraldehyde-polymerized) renal MT while renal GSH levels were determined by fluorimetry. At 90, 300, 600, and 720 days, dwarf renal MT and GSH levels were significantly higher than controls. Interestingly, TEM morphometry data demonstrated that with increasing age, both the GBMs and TBMs of dwarf animals were thinner (1.1–15.7% and 28.8–45.5%, respectively) than those of age-matched controls. Since MT and GSH are well-documented ROS scavengers, it seems possible that in the Ames dwarf model of delayed aging, increased endogenous antioxidant levels provide renoprotection from oxidative damage and lead to reduced rates of age-related GBM and TBM thickening.