Role of vascular functional and structural alterations in the development and maintenance of hypertension in chronic kidney disease

Cardiovascular disease is markedly increased in patients with advanced kidney disease and is associated with changes in vascular function (Sutliff et al., 2011). Chronic kidney disease (CKD) patients often die due to cardiovascular complications prior to complete renal failure; however little attention is focused on the structure and function of hypertensive large arteries, which greatly influence the development of complications in hypertensive vascular disease (Safar et al., 2004). Here, our investigations aimed to: 1) investigate the role of sympathetic activity and the vascular amplifier effect in CKD; 2) explore structural aortic stiffness; 3) investigate functional responses of the aorta; and 4) investigate the effect of angiotensin II (Ang II) blockade on aortic function and structure. To conduct our investigations, we employed an established rat model of CKD, the Lewis polycystic kidney (LPK) rat. The LPK exhibit sympathetic hyperactivity (Phillips et al., 2007, Hildreth et al., 2013, Salman et al., 2013), increased functional aortic stiffness measured by pulse wave velocity in vivo, and aortic calcification and remodelling (Salman et al., 2013, Ng et al., 2011b, Ng et al., 2011a). Firstly, we investigated whether a great level of sympathetic hyperactivity accounts for an enhanced depressor response to ganglionic blockade in the LPK, or whether it reflects increased sensitivity of arterial pressure to vasoactive agents (vascular amplifier effect). Urethane-anaesthetised LPK, spontaneously hypertensive rats (SHR: a hypertensive control for LPK) and Lewis control rats were examined for depressor response to ganglionic blockade (hexamethonium) and direct vasodilators (sodium nitroprusside and adenosine). Experiments revealed that hexamethonium produced a greater depressor response in both the LPK and SHR compared with Lewis, and that the relationship between blood pressure (BP) and low frequency power of systolic BP variability was greater in the LPK compared with Lewis. Thus, study 1 showed that in the LPK under an in vivo setting, sympathetic vasomotor tone exhibited greater role in driving the high BP state than an exaggerated contribution of the amplifying response of the vasculature. Study 2 examined regional aortic biomechanical and structural properties in the LPK, vitamin D3/nicotine (VDN) model of induced vascular calcification in normotension, SHR, and Lewis and Wistar-Kyoto (WKY) controls. Local (thoracic and abdominal) aortic stiffness was quantified using tensile testing in vitro, while aortic elastin, collagen, and calcification were evaluated histologically. Results showed that LPK and VDN thoracic aorta had higher breaking strain, while the opposite was seen in the abdominal aorta of the LPK, along with reduced breaking stress. Reduced elastin and/or increased collagen proportional densities were only evident in the LPK. In addition, abdominal aortic regions of LPK and VDN rats exhibited accelerated stiffening not seen in the thoracic aorta. Thus, study 2 showed that regionally distinct BP-independent effects of calcification and arteriosclerosis are evident in LPK aorta. Study 3 assessed the hypothesis that a temporal deterioration in vascular function parallels decline in renal function. Here, aortic organ bath studies and mRNA investigations of stiffness and oxidation markers were carried out to compare LPK at 12 and 18 weeks of age relative to Lewis controls. Results showed that maximum constriction and endotheliumdependent and -independent relaxations were impaired in all LPK, and that aortic sensitivity to noradrenaline (NA) was increased in the older LPK. When nitric oxide synthase (NOS) precursor and inhibitor were combined, NOS activity was recovered in the 12, but not 18 weeks LPK, indicating an age-dependent decrease in NOS activity. Study 3 further showed an increase in markers of aortic stiffness and oxidative state in the LPK, and that endothelial dysfunction in CKD is possibly driven by progressive deficits in NOS activity. To investigate whether Ang II contributes to the observed vascular abnormalities and endothelial dysfunction, in study 4 we treated LPK and Lewis rats with an Ang II receptor blocker, valsartan, from 4-18 weeks of age. Valsartan reduced BP and left ventricular hypertrophy, and ameliorated aortic wall hypertrophy, elastin degradation and calcification. Functionally, aortic sensitivity to NA was ameliorated, endothelium-dependent and -independent deficits corrected, and the negative association between uraemia and impaired vasorelaxation in the LPK abrogated. Thus, Ang II seems to have a detrimental impact on aortic function and structure with progressive end-stage renal disease (ESRD). Therefore, these results collectively indicate that vascular changes influenced by both neuronal and hormonal pathways including SNS and Ang II respectively are likely key contributors to high BP in CKD. Furthermore, aortic stiffening along its structure is highly driven by altered arterial wall composition and calcification. Increased sensitivity to contractile signals, reduced compliance and vasorelaxation, and endothelial dysfunction are evident vascular pathologies that relate to CKD progression. Identifying these pathophysiological mechanisms can aid in therapeutic targeting and reduction of cardiovascular risks in the CKD.