Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.

Vasopressin-related copeptin is a novel predictor of early endothelial dysfunction in patients with adult polycystic kidney disease

“…Consistent with this finding, Lothioir et al [21] recently reported that FMD induced by warm-ischemia, but not that induced by NO, is impaired in ADPKD. Studying 21 normotensive patients (eGFR 99 ± 18 mL/min/1.73 m 2 , 36% smokers) they found a maintained ability to dilate vessels following infusion of an NO-donor, while warm ischemia led to a markedly blunted response in patients as compared to controls.…”

Flow-mediated dilation stimulated by sustained increases in shear stress: A useful tool for assessing endothelial function in humans?

“…Autosomal dominant polycystic kidney disease patients have cardiovascular complications that are thought to be related to the presence of abnormal polycystins in endothelial cells that may interfere with shear stress mechanotransduction; however, there are conflicting findings regarding whether patients with autosomal dominant polycystic kidney disease present conduit artery endothelial dysfunction as assessed by RH-FMD (15,50). Lorthioir et al (56) performed radial artery RH-FMD and hand-warming SS-FMD in patients with autosomal dominant polycystic kidney disease and observed an impaired SS-FMD but similar RH-FMD compared with control subjects with no difference in the shear stress stimuli (SS or RH) between groups. Thus patients with autosomal dominant polycystic kidney disease may have impairments in mechanotransduction of sustained, but not necessarily transient, shear stress.…”

Primary Cilia are Sensory Hubs for Nitric Oxide Signaling

“…It was shown that ADPKD patients had significantly less vasodilation during sustained flow increases, as well as a total loss of NO release when compared to those without ADPKD. When ADPKD patients were administered brachial infusions of 0.25-0.5 μg/kg/min of dopamine, there was an increase in flow-mediated dilation, and a statistically significant increase in dilatory response at the highest dose [80]. According to these results, dopamine receptors may facilitate a connection between primary cilia, NO, and blood pressure regulation in ADPKD patients [1].…”