Sexual dimorphism in glomerular arginine transport affects nitric oxide generation in old male rats

Animal models suggest that decreased renal endothelial nitric oxide synthase (eNOS) activity in old males promotes renal injury, whereas females are protected. We aimed to explore whether aging alters glomerular arginine uptake by CAT-1, the selective arginine supplier to eNOS in rats. Arginine uptake by glomeruli from young males (3 mo) was significantly higher than in young females. Old males (19 mo) exhibited a significant decrease in arginine transport compared with young males, whereas no differences were observed between old and young females. CAT-1 abundance remained unchanged in all experimental groups. The abundance of PKCalpha (CAT-1 inhibitor) was significantly augmented in young females vs. young males, old vs. young males, and in old females vs. old males. No differences in PKCalpha content were detected between old and young females. Phosphorylated PKCalpha was significantly increased in old rats from both genders. alphaTocopherol, a PKC inhibitor, produced a significant increase in arginine transport and restored NO generation in old males only. Ex vivo incubation of glomeruli from old males with PMA (PKC stimulant) significantly attenuated the effect of tocopherol on arginine uptake. In conclusion, attenuated glomerular arginine transport by CAT-1 contributes to the age-dependent, NO-deficient state in old male rats through upregulation of PKCalpha. In old females glomerular arginine transport is protected from the effects of PKCalpha by an unknown mechanism.