Abstract
Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (Rmax) to noradrenaline at 12 and 18 weeks, and to K+ (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 × 10−9 ± 78 × 10−10 vs. 19 × 10−8 ± 49 × 10−9, P < 0.05). Endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks Rmax: 80 ± 8% vs. 57 ± 9% and 92 ± 6% vs. 70 ± 9%, P < 0.05, respectively) in parallel with the decline in renal function. L-Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling.
Highlights
Individuals with chronic kidney disease (CKD) are at high risk of cardiovascular disease (Kuznik et al, 2013) with renal failure and the accumulation of uraemic toxins proposed to stimulate oxidative stress and inflammation that in turn may contribute to endothelial dysfunction (Schiffrin et al, 2007)
At 18 weeks in the Lewis polycystic kidney (LPK) animals, the addition of the nitric oxide synthase (NOS) substrate did not alter the EC50 but did result in a greater area under curve (AUC) compared with responses in the presence of acetylcholine hydrochloride (ACh) alone (Figure 3D, Table 3). (2) Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME): L-NAME markedly blunted the ACh-mediated responses in all groups (Figures 3A–D), reduced maximum aortic vasoconstriction (Rmax) was lower in the presence of L-NAME than in the presence of ACh alone at all strains and ages (Table 3)
We have previously shown that the thoracic aorta from the LPK rodent model of CKD exhibits significant remodeling (Ng et al, 2011; Ameer et al, 2014) and in this study we aimed to determine if aortic vascular functional responses declined in parallel with measures of renal dysfunction and examined potential underlying mechanisms
Summary
Individuals with chronic kidney disease (CKD) are at high risk of cardiovascular disease (Kuznik et al, 2013) with renal failure and the accumulation of uraemic toxins proposed to stimulate oxidative stress and inflammation that in turn may contribute to endothelial dysfunction (Schiffrin et al, 2007). Significant changes in large artery viscoelasticity resulting in altered reactivity, reduced compliance and increased arterial stiffness have been reported among haemodialysis patients (London et al, 1990) and damage to the large capacitive arteries like the aorta is considered an important factor contributing to increased morbidity and mortality in end stage renal disease (ESRD) (Blacher et al, 1999; Pannier et al, 2005; Guérin et al, 2008). This suggests a pivotal role for the aorta in driving both systemic and/or organ dysfunction. Aortic structure and function, as a crucial component of the cardiovascular system, can affect and be affected by kidney disease (Bakris et al, 2003; Mitchell, 2008)
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