Uric acid, Cardiovascular Function, and the Kidney

Uric acid (UA) is the end-product of purine metabolism in human. The most common clinical manifestation of elevated circulating UA level, i.e. hyperuricemia, is gout, an inflammatory arthritis typically manifesting in the first metatarsophalangeal joint. Epidemiological studies have rather unambiguously indicated that the prevalence of hyperuricemia is increasing worldwide. This increase has co-occurred with lifestyle westernization and higher incidence of chronic kidney disease (CKD), and cardiovascular morbidities such as hypertension, type 2 diabetes, and atherosclerosis, suggesting a possible role of UA in the development of these diseases. It is still not clear, however, whether UA itself plays a role in these conditions, or is secondary to reduced renal UA excretion and oxidative stress, both elevating circulating UA levels. The ability of UA to provide protection against oxidant damage in certain neurological conditions challenges the view of UA being harmful contributor in disease pathophysiology.

To investigate the role of UA in cardiovascular and renal diseases, an experimental model of dietary 2% oxonic acid (inhibitor of uric acid degrading uricase-enzyme)-induced hyperuricemia has been developed. The model rather closely simulates the hyperuricemic state in humans, in whom a mutation early in the evolution has resulted in higher UA levels than in most other mammals. Previous experimental studies with rather short durations and heterogenic study protocols have suggested that UA contributes to the progression of cardiovascular and renal diseases by causing intrarenal inflammation, oxidative stress, and depletion of endothelium-derived vasodilator nitric oxide (NO). Synergistically, these changes have been suggested to cause glomerular vascular disease, hypertension, and ultimately renal fibrosis. The contribution of UA to the systemic vascular function, morphology, and renal histology in relation to the prevailing oxidant status has not been previously elucidated.

Reduced compliance of the large arteries, as indicated by increased pulse wave velocity (PWV), is considered as an independent indicator for higher cardiovascular risk. In some clinical studies, higher UA levels have been independently associated with increased PWV, while other studies have not supported this view. Thus, the knowledge over the role of UA in human hemodynamics is largely unknown.

The experimental part of the study (studies I, II, III) examined the cardiovascular and renal effects of nine week-long oxonic acid (Oxo) induced hyperuricemia in healthy (Sham) and surgically 5/6 nephrectomized (NX) rats (n=12/group). The focus was to investigate the mesenteric and carotid artery functional responses, small mesenteric artery morphology, cardiac volume load, systemic and renal oxidative stress, and kidney markers of fibrosis and inflammation. The vascular studies were performed in vitro with isolated arterial rings by recording the changes in small artery tone in response to different pharmacological vasoactive agents by using a myograph. Cardiac load was assessed by measuring cardiac natriuretic peptide mRNA content, while systemic oxidative stress markers and antioxidant status were evaluated in vivo by measuring urinary excretion of 8-isoprostaglandin F2α and 11- epi-prostaglandin F2α and plasma total peroxyl radical-trapping capacity (TRAP). Indices of renal damage (histology, proteinuria, mast cell count), inflammation (cyclooxygenase-2, COX-2), and oxidative stress (heme oxygenase-1, HO-1) were evaluated microscopically, immunohistochemically, and by using Western blotting and real time quantitative PCR (RT-PCR), as appropriate. The clinical study (study IV) examined non-invasively by using whole-body impedance cardiography and radial tonometric pulse wave analysis the association of plasma UA concentration with several hemodynamic variables, including PWV. The study participants consisted of 606 normotensive or never-medicated hypertensive asymptomatic individuals with plasma UA levels predominantly within the normal range.

The results from the experimental study replicated several characteristics of moderate CKD: mild hypertension and cardiac load, impaired endothelium- mediated vasorelaxation in the mesenteric and carotid artery, hypertrophic remodeling of the small mesenteric artery, renal fibrosis, proteinuria, and increased oxidative stress. In experimental CKD, hyperuricemic milieu improved NO- mediated carotid artery vasorelaxation, but in parallel endothelium-independent vasorelaxation mediated via smooth muscle cell hyperpolarization in the main branch of the mesenteric artery was impaired. Congruently, hyperuricemic remnant kidney rats displayed improved kidney morphology and reduced markers of inflammation. Systemic and renal markers of oxidative stress were reduced, and plasma TRAP increased in hyperuricemia, but UA did not significantly influence blood pressure, cardiac load, or small mesenteric artery morphology. In the clinical study, plasma UA concentration was independently associated with large arterial stiffness in both sexes, but not with blood pressure or any other hemodynamic variable including cardiac output, systemic vascular resistance, or wave reflection.

The present series of experimental studies adds further knowledge to the mechanisms via which UA mediates its effects in the cardiovascular system and in the kidney. In experimental CKD, hyperuricemia associated with improved renal morphology and NO-mediated carotid artery vasorelaxation, in association with more favorable oxidant/antioxidant status both in vivo and in the kidney. The results from the clinical study support the view that in normotensive and never-medicated hypertensive individuals, the association of higher UA levels with increased cardiovascular risk might be mediated via reduced compliance of the large arteries. Collectively, these results demonstrate the dual actions of UA in different species and in physiological versus in vitro milieus. Prospective longitudinal studies exploring the hemodynamic effects of hyperuricemia are warranted in the future.