Impaired L‐arginine Uptake Contributes to Aortic Endothelial Dysfunction in Chronic Kidney Disease

Reduced nitric oxide (NO) bioavailability contributes to endothelial dysfunction in chronic kidney disease (CKD) and is related to an increased cardiovascular disease risk. Vascular uptake of the NO substrate L‐arginine is attenuated under uremic conditions and may be an important mechanism of endothelial dysfunction in CKD. We sought to determine if impaired L‐arginine transport contributed to endothelial dysfunction in an animal model of CKD. 12 week old, male Sprague‐Dawley rats underwent 5/6 ablation/infarction (AI) surgery to induce CKD and were compared to a Sham control group. Endothelial‐dependent relaxation (EDR) of aortic rings to acetylcholine (Ach; 10 −9 –10 −5 M) was significantly impaired in AI vs. Sham after 8 weeks, demonstrated by an attenuated maximal response (65.02±5.02 vs. 102.10±4.94%, p < 0.0001) and rightward shifted LogEC50 (−6.659±0.121 vs. −7.707±0.111, p<0.0001) and was not improved by L‐arginine treatment. In support of this finding, expression of the L‐arginine transporter CAT‐1 was attenuated in CKD (relative to β‐actin, p=0.002) and appears to have resulted in reduced aortic uptake of L‐[ 3 H]arginine (49.01±15.48 vs. 100.08±16.33 dpm/mg, p = 0.06). These preliminary data suggest that uremic inhibition of L‐arginine uptake may act as a novel mechanism by which endothelial dysfunction occurs in CKD and may be a potential therapeutic target to treat vascular dysfunction in CKD. Supported by: P20 RR016472