Role of resistance vasculature in the development and maintenance of hypertension in chronic kidney disease
thesisposted on 28.03.2022, 18:07 by Ko Jin Quek
Hypertension is a significant complication among chronic kidney disease (CKD) patients, resulting in higher mortality rates in these patients than renal disease itself. The process of cardiovascular damage starts very early during progression in well-defined CKD, long before the renal treatment stage is reached (Vanholder et al., 2005), thus making kidney disease the most common “secondary” form of hypertension (Cohen and Townsend, 2009, Ross and Banerjee, 2013). Resistance arteries play a particularly important role in the maintenance of hypertension in these CKD patients (Li et al., 1997, Paisley et al., 2009), as they are the main contributors to total peripheral resistance (TPR) (Beevers et al., 2001, Mulvany et al., 1978, Mulvany and Halpern, 1977). Although it is well-established that alterations in resistance arteries are likely to contribute to increased cardiovascular risk and act as a substrate for end-organ damage (Schiffrin, 2012), resistance artery alterations are still poorly understood in the CKD-mediated hypertensive state, and hence were the focus of this thesis. To investigate the effects of CKD on the resistance vasculature as part of the overall cardiovascular disease (CVD) state, we employed an established rat model of CKD-mediated hypertension, the Lewis polycystic kidney (LPK) rat. In a series of four studies, we sought to examine alterations in resistance artery structure, function and biomechanical properties, in association with disease progression. In addition, we investigated the effects of treatment (AT1 receptor antagonism and calcium channel blockade) on the resistance vasculature. In study 1, we explored temporal changes in LPK resistance artery structure, function and biomechanical properties, in association with hypertension and renal disease progression. We investigated three time-points: 6 weeks of age, where LPKs are hypertensive and have gross derangement of the kidney cortex and medulla; 12 weeks of age, where LPKs demonstrate signs of renal dysfunction in addition to hypertension and increased sympathetic nerve activity (SNA); and 18 weeks, where LPK have marked renal disease and still present with hypertension and elevated SNA (Phillips et al., 2007). These experiments revealed that alterations in the vasculature tended to emerge after the 6 week time-point in LPK, and that older age was associated with negative outcomes. Older LPK resistance arteries underwent structural alterations which were characterised by eutrophic and hypertrophic inward remodelling at established and severe renal disease time points, respectively, and these structural alterations were significantly associated with the hypertension. Stiffness was increased in 6 and 18 week LPK, and impaired endothelium-dependent relaxation was evident in 12 and 18 week LPK. These findings suggested that in CKD-mediated hypertension, multiple effects on resistance arteries are seen, which result in the activation of compensatory mechanisms: structural mechanisms eventually become maladaptive, thus exacerbating the disease, while functional mechanisms involve endothelial dysfunction, impairing vasorelaxation. Thus, study 1 revealed that impairments in the LPK vasculature arise at as early as 6 weeks, and generally worsen as hypertension pursues and with progression to marked renal disease. Study 2 aimed to ameliorate the deleterious alterations in the vasculature found in study 1, via treatment with an angiotensin type 1 (AT₁) receptor antagonist, valsartan, to block the effects of angiotensin II (Ang II). Chronic treatment performed from 4-18 weeks of age reduced hypertension, improved collagen-elastin ratios and structural vascular remodelling outcomes. In addition, LPK treated with valsartan exhibited vasoconstriction and vasorelaxation responses that were comparable to Lewis controls, and demonstrated improved stiffness and compliance properties. Thus, study 2’s findings highlighted the important contribution of Ang II and AT₁ receptors to resistance artery structural, functional and biomechanical properties Similar to study 2, study 3 also aimed to ameliorate the deleterious alterations in vasculature found in study 1. However, in addition to this, study 3 aimed to further investigate whether valsartan’s effectiveness was due to the specific blockade of Ang II’s effects, or because of the resultant reduction of blood pressure. Hence, study 3 involved treatment of LPK rats with amlodipine to block the effects of voltage-dependent L-type Ca²⁺ channels (LTCCs), and therefore result in an antihypertensive effect without directly affecting Ang II signalling. Similar to valsartan outcomes, chronic treatment with amlodipine performed from 4-18 weeks of age reduced hypertension, improved collagen-elastin ratios, improved structural vascular remodelling outcomes, and normalised dysfunctional vasoconstriction and vasorelaxation responses in LPK. However, relative to valsartan, the effectiveness of amlodipine in normalising these parameters was to a lesser extent. In addition, amlodipine was unable to improve stiffness and compliance properties in LPK rats. In study 4, we investigated myogenic tone and endothelial dysfunction, examining sensitivity to endothelial-derived constricting and relaxing factors. In addition, because endothelial dysfunction has been shown to be receptor-specific, we investigated the effect of different agonists on endothelial responses. Study 4 revealed increased myogenic tone and vasoconstriction to Ang II in LPK rats, along with endothelial dysfunction that correlated with the degree of renal impairment, regardless of the agonist used (bradykinin, BK; or aceylcholine, ACh). Collectively, these studies showed that hypertension and renal impairment in a rat model of CKD are associated with alterations in the mesenteric resistance arteries, and that pharmacological treatments are able to mitigate the majority of these observed changes. These modifications of structural, functional and biomechanical resistance artery properties serve to protect end-organs by mediating pressure changes; however, with the persistence of both hypertension and renal dysfunction, these changes can ultimately lead to further exacerbation of these disease states. Overall, these studies provide a better understanding of the pathological resistance vasculature consequences in the CVD and CKD states, and thus help to direct pharmacological targets for more effective therapeutic outcomes.