Abstract 1498: Imbalance Among Angiotensin II Receptors, Nitric Oxide System, and Manganese Superoxide Dismutase in the Aging Kidney
Chronic kidney disease (CKD) prevalence increases with aging. We hypothesized that age-related renal injury is associated with alterations in the relative expression of angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors, nitric oxide (NO) system, and the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD). Compared to 3 month (mo) old, 24 mo male Sprague Dawley rats manifested glomerulosclerosis and interstitial fibrosis with increased TGFβ mRNA (real-time PCR, 1.2±0.07 vs. 1±0.03; P<0.05) and protein expression (Western blot) of cycloxygenase (COX)-2 (3-fold) and fibronectin (7-fold). Cortical AT1R protein expression was similar but AT2R was decreased in 24 mo (0.58±0.07 vs. 1±0.07; P<0.01), whereas medullary AT1R was increased in 24 mo (1.9±0.3 vs. 1±0.1; P<0.02) but AT2R was similar. Cortical and medullary AT1R/AT2R ratios were increased in 24 mo. Cortical endothelial NO synthase (eNOS) protein expression was similar, but medullary eNOS was decreased in 24 mo (0.5±0.02 vs. 1±0.14; P<0.01). eNOS dimer/monomer ratio was similar, suggesting that the enzyme is not uncoupled. Inducible NOS (iNOS) protein expression was not significantly elevated in 24 mo. The mitochondrial enzyme arginase II competes with NOS for arginine. Cortical protein expression of arginase II was decreased in 24 mo (0.5±0.08 vs. 1±0.18, P=0.05), whereas medullary arginase II was similar. NADPH oxidase activity was similar, but cortical (0.6±0.06 vs. 1±0.13; P=0.01) and medullary (0.4±0.1 vs. 1±0.2; P<0.03) protein expression of MnSOD were decreased in 24 mo. Age-related renal injury was associated with increased renal AT1R/AT2R ratio, decreased MnSOD, as well as alterations in eNOS and arginase II expression. Decreased MnSOD may increase the vulnerability of mitochondria to oxidant injury and reduction in the relative expression of intrarenal AT2R and eNOS may amplify AT1R-mediated effects on oxidative stress, vasoconstriction, matrix deposition and cell growth. CKD is a significant risk factor for cardiovascular morbidity and mortality. Since the majority of patients treated for CKD are from the elderly population, an understanding of the molecular changes that occur in the aging kidney is necessary to develop therapies that slow renal damage.
This research has received full or partial funding support from the American Heart Association, AHA National Center.