Abstract 10044: Hyperphosphatemia Causes Endothelial Dysfunction by Inhibiting Akt-Endothelial Nitric Oxide Synthase Pathway in Chronic Kidney Disease Rats
Hyperphosphatemia is an independent risk factor for cardiovascular disease in the chronic kidney disease (CKD) patients. Recent reports suggest that elevation of extracellular phosphate (P) level can be involved in endothelial dysfunction by inhibiting endothelial nitric oxide synthase (eNOS). However the exact mechanism of the hyperphosphatemia-mediated inhibition of eNOS has not been clarified. In this study we investigated how hyperphosphatemia can inhibit eNOS activity, and whether correcting serum P level can improve the inhibition in the adenine-induced CKD model rats. Administration of 0.75% adenine-containing diet for 3 weeks caused CKD with hyperphosphatemia in Sprague-Dawley rats. The CKD rats also revealed impaired acetylcholine-dependent vasodilation of thoracic aortic ring with inhibition of phosphorylations of eNOS at serine 1177 and Akt at serine 473. Then we treated the CKD rats with low-P diet (LPD; 0.2%P) or control diet (CPD; 1.0%P) for 16 days. The treatment with LPD significantly improved plasma P levels, acetylcholine-dependent vasodilation of thoracic aortic ring, and also improved the phosphorylations of eNOS and Akt compared to CPD-treated rats. There was no significant difference in plasma creatinine, blood urea nitrogen, and asymmetric dimethylarginine between LPD and CPD groups. Akt is important for the phosphorylation of eNOS at serine 1177. The treatment of LPD corrected serum P level and endothelial function without improvement of kidney dysfunction. Therefore, we conclude that hyperphosphatemia primarily impaired endothelial function by inhibiting Akt-eNOS signal pathway in the CKD model rats.
- © 2011 by American Heart Association, Inc.