Voluntary wheel running augments aortic l-arginine transport and endothelial function in rats with chronic kidney disease

Abstract

. Voluntary wheel running augments aortic L-arginine transport and endothelial function in rats with chronic kidney disease. Am J Physiol Renal Physiol 307: F418 -F426, 2014. First published June 25, 2014 doi:10.1152/ajprenal.00014.2014.-Reduced nitric oxide (NO) synthesis contributes to risk for cardiovascular disease in chronic kidney disease (CKD). Vascular uptake of the NO precursor L-arginine (ARG) is attenuated in rodents with CKD, resulting in reduced substrate availability for NO synthesis and impaired vascular function. We tested the effect of 4 wk of voluntary wheel running (RUN) and/or ARG supplementation on endotheliumdependent relaxation (EDR) in rats with CKD. Twelve-week-old male Sprague-Dawley rats underwent 5 ⁄6 ablation infarction surgery to induce CKD, or SHAM surgery as a control. Beginning 4 wk following surgery, CKD animals either remained sedentary (SED) or received one of the following interventions: supplemental ARG, RUN, or combined RUNϩARG. Animals were euthanized 8 wk after surgery, and EDR was assessed. EDR was significantly impaired in SED vs. SHAM animals after 8 wk, in response to ACh (10 Ϫ9 -10 Ϫ5 M) as indicated by a reduced area under the curve (AUC; 44.56 Ϯ 9.01 vs 100 Ϯ 4.58, P Ͻ 0.05) and reduced maximal response (Emax; 59.9 Ϯ 9.67 vs. 94.31 Ϯ 1.27%, P Ͻ 0.05). AUC was not improved by ARG treatment but was significantly improved above SED animals in both RUN and RUNϩARG-treated animals. Maximal relaxation was elevated above SED in RUNϩARG animals only. L-[ 3 H]arginine uptake was impaired in both SED and ARG animals and was improved in RUN and RUNϩARG animals. The results suggest that voluntary wheel running is an effective therapy to improve vascular function in CKD and may be more beneficial when combined with L-arginine. endothelial dysfunction; chronic kidney disease; L-arginine; exercise ENDOTHELIAL DYSFUNCTION CONTRIBUTES to the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) and is primarily associated with a decrease in nitric oxide (NO) production and impaired endothelium-dependent relaxation (EDR) (32). The decline in endothelial function precedes the development of atherosclerosis (17, 48) and has been extensively studied as a potential therapeutic target to treat CVD; however, the specific mechanisms of endothelial dysfunction in CKD have not been fully elucidated. Patients with CKD are more likely to die of CVD than progress to end-stage renal disease (26, 42); therefore, novel treatments to improve endothelial function in CKD are needed to reduce CVD-related mortality in CKD.Insufficient availability of the NO precursor L-arginine likely contributes to reduced NO synthesis in CKD (6). Interestingly, the use of L-arginine in studies of endothelial dysfunction in late-stage CKD has produced mixed results (7, 16) unlike other conditions where it has been largely effective (8,13,15,24). Evidence from cell culture studies suggests that urea and other uremic toxins inhibit L-arginine uptake into endothelial cells (52, 54) by...

The Vascular Endothelium in Chronic Kidney Disease

“…The mechanisms by which aerobic exercise training improves endothelial function in CVD are multifaceted, but are largely associated with an increase in endothelial NO bioavailability. Recent evidence from our own work supports the novel hypothesis that aerobic exercise training improves endothelial function in CKD by reversing impairments to the L-arginine transport system, thus facilitating substrate delivery for NO production (23). Due to the body of literature suggesting that endothelial dysfunction becomes increasingly more difficult to reverse in advanced CKD, aerobic exercise training may represent a novel adjunctive therapy to treating endothelial dysfunction in CKD.…”

“…In support of this hypothesis, 8 weeks of aerobic exercise training has been shown to improve L-arginine uptake by the forearm microvasculature in patients with congestive heart failure (29). We have recently extended these findings to an animal model of CKD in which we demonstrated improved L-arginine transport activity in response to 8 weeks of very low volume voluntary wheel running, a model of regular aerobic exercise training (23). …”

“…Evidence from our own work suggests that the increase in L-arginine transport by voluntary wheel running is not associated with an increase in CAT-1 abundance, but rather through an increase in L-arginine transport activity (23). Thus, the regulation of L-arginine transport by aerobic exercise training likely occurs at the post-translational level, presumably through modification of CAT-1.…”

“…To compensate for the decrease in endogenous L-arginine synthesis, treatment with exogenous L-arginine has been explored in the context of endothelial function; however, this approach has been met with mixed results. Dietary supplementation with L-arginine has been shown to prevent the development of endothelial dysfunction in an animal model of CKD when initiated immediately following disease induction (40); however, we have recently demonstrated that oral supplementation with L-arginine does not reverse endothelial dysfunction in animals once CKD has already been established (23). These findings are mirrored by acute infusion studies in humans in which exogenous L-arginine improved vasodilation in the skin microvasculature of patients with moderate CKD (8) but did not restore endothelial function in the forearm microvasculature of patients with severe renal failure (7).…”

“…Aerobic exercise is a well-known stimulus for improving endothelial function in CVD and limited but compelling evidence from animal studies suggests that exercise may have similar beneficial effects on endothelial function in CKD (1, 23, 37). The mechanisms by which aerobic exercise training improves endothelial function in CVD are multifaceted, but are largely associated with an increase in endothelial NO bioavailability.…”