Endothelial Dysfunction Occurs prior to Clinical Evidence of Polycystic Kidney Disease

Abstract

Objective: Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end-stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and its relationship with renal dysfunction remain to be determined. Methods: ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied. Results: Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in mean arterial pressure or renal function. The abnormal vasoreactivity was corrected with <smlcap>L</smlcap>-arginine (a precursor of nitric oxide, NO), while the expression of endothelial NO synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6-week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively). Conclusion: ARPKD leads to impairments in aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.

Early Markers of Cardiovascular Risk in Autosomal Dominant Polycystic Kidney Disease

“…Indeed, endothelial dysfunction is an early and potentially reversible manifestation of atherosclerosis, with multifactorial etiology [52-54], and it develops in ADPKD patients, preceding the renal failure [55-56]. Atherosclerosis has been considered to play a key role in the early phases of cardiovascular disease found in ADPKD [57-59]. Cardiopulmonary exercise testing is considered the gold-standard for assessment of cardiorespiratory fitness.…”

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

“…Based on our findings, vascular dysfunction in ADPKD is related to endothelial function (FMD) and potentially atherosclerosis (cIMT) more than to fluid overload (PWV) or cardiac failure (echocardiography). We [16, 17] and others [18, 19] have previously reported an impaired vascular function during early-stage ADPKD in cross-sectional studies and single modalities assessing vascular functions, while Peterson et al [20] studied endothelium-dependent vasodilation in a rat model of ADPKD and reported changes there that preceded a rise in mean arterial pressure or drop in GFR. With the present data, these findings are extended and broadened, demonstrating the consistent nature of ADPKD vasculopathy (early onset, FMD worse than cIMT, which in turn is worse than PWV and precedes any changes in cardiac geometry) as well as the extent to which vascular decline precedes that of GFR and also develops at a faster rate.…”

The functions of TRPP2 in the vascular system

“…Karen et al have found that the aorta in an autosomal recessive ARPKD animal model had abnormal endothelium-dependent vascular reactivity, likely due to a primary defect in the endothelial cells that occurred prior to the changes in mean arterial pressure or renal function. However, the endothelium-independent relaxation, for example, that in smooth muscle cells, was not impaired [19] .…”

“…Mutation of the PKD2 gene is a major cause of autosomal dominant polycystic kidney disease (ADPKD), which is a common genetic disease of the kidney [18] . However, patients with ADPKD suffer from not only a defect in kidney function but also a systemic disorder associated with abnormalities in the vasculature, such as cerebral, intracranial, and aortic aneurysms and cardiac valvular dysfunction [19][20][21] . Therefore, cardiovascular complications are typically the leading cause of mortality and morbidity in ADPKD patients [22][23][24][25][26] .…”