Pkd2 mesenteric vessels exhibit a primary defect in endothelium-dependent vasodilatation restored by rosiglitazone

Abstract

Patients with autosomal dominant polycystic kidney disease have a high prevalence of hypertension and structural vascular abnormalities, such as intracranial aneurysms. Hypertension can develop in childhood and often precedes a significant reduction in the glomerular filtration rate. The major aim of this study was to investigate whether a primary endothelial defect or a vascular smooth muscle (VSM) defect was present in murine polycystic kidney disease (Pkd)2 heterozygous mesenteric vessels before the development of renal failure or hypertension. Using pressure myography, we observed a marked defect in ACh-stimulated endothelium-dependent vasodilatation in Pkd2 arterioles. In contrast, Pkd2 vessels responded normally to sodium nitroprusside, phenylephrine, KCl, and pressure, indicating unaltered VSM-dependent responses. Pretreatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone significantly restored ACh-dependent vasodilation in Pkd2 mice. Isolated heterozygous Pkd2 endothelial cells displayed normal ACh-stimulated Ca(2+) and nitric oxide production. However, isolated Pkd2 heterozygous VSM cells displayed basal increases in superoxide and sodium nitroprusside-stimulated peroxynitrite formation, which were both suppressed by rosiglitazone. Furthermore, we observed a defective response of Pkd2 mesenteric venules to ACh in vivo, which was more marked after ischemia-reperfusion injury. In conclusion, the results of our study suggest that the defect in vasodilatation in Pkd2 heterozygous vessels is primarily due to a reduction in nitric bioavailability secondary to increased vascular oxidative stress. The ability of rosiglitazone to correct this phenotype suggests that this defect is potentially reversible in patients with autosomal dominant polycystic kidney disease.

Elevated Asymmetric Dimethylarginine is Associated With Oxidant Stress Aggravation in Patients With Early Stage Autosomal Dominant Polycystic Kidney Disease

“…Reduced anti-oxidant protection of the cysteine residue in the reactive site of DDAH can result in decreased DDAH activity and elevated circulating levels of ADMA during oxidative stress [28,29]. The link between oxidative stress and endothelial dysfunction in ADPKD is also supported by a recent experimental study [30] in mice with polycystic kidney disease 2. In that work, the acetylcholine-stimulated endothelium-dependent vasodilatation in isolated arterioles was impaired and accompanied by elevated basal superoxide and sodium nitroprusside-stimulated peroxynitrite formation in isolated vascular smooth muscle cells (VSMC), whereas these defects were reversible after the administration of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone [30].…”

Lower-limb veins are thicker and vascular reactivity is decreased in a rat PCOS model: concomitant vitamin D3treatment partially prevents these changes

“…A significantly lower expression of eNOS and nNOS has been shown in varicose veins as a result of chronic venous stasis, which suggested to the authors that mechanisms other than NO release should be involved in pathological dilation (8). Decreased bioavailability might contribute according to observations on mesenteric venules by Brookes et al (2), who found that increased vascular oxidative stress limited the effect of NO. The insulin resistance previously observed in PCOS (21,31) can also interfere with the NO pathway (38).…”

“…The saphenous veins were allowed to equilibrate for 30 min at 5-mmHg intraluminal pressure in an oxygenized nKR solution. After incubation, the pressure was first decreased to 2 mmHg and then increased to 20 mmHg in steps (2,4,6,8,10,15, and 20 mmHg). The steady-state diameter at each step was measured.…”

Clinical Manifestation, Management and Prognosis of Acute Myocardial Infarction in Autosomal Dominant Polycystic Kidney Disease

“…An inverse correlation between serum high-density lipoprotein levels and both the rate of kidney growth and the decline in glomerular filtration rate has been observed in ADPKD patients [30]. Furthermore, several clinical studies have demonstrated that oxidative modification of low-density lipoprotein in patients with early stage ADPKD can drive the deterioration of renal function and hypertension [31, 32]. Consequently, ADPKD patients exhibit more severe coronary lesions and more frequently undergo CABG.…”