TY - JOUR
T1 - Endothelial dysfunction occurs prior to clinical evidence of polycystic kidney disease
AU - Peterson, Karen M.
AU - Franchi, Federico
AU - Loeffler, Darrel L.
AU - Psaltis, Peter J.
AU - Harris, Peter C.
AU - Lerman, Lilach O.
AU - Lerman, Amir
AU - Rodriguez-Porcel, Martin
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/9
Y1 - 2013/9
N2 - 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 L-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.
AB - 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 L-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.
KW - Acetylcholine
KW - Autosomal inheritance
KW - Cardiovascular disease
KW - Endothelial dysfunction
KW - Polycystic kidney disease
UR - http://www.scopus.com/inward/record.url?scp=84885032006&partnerID=8YFLogxK
U2 - 10.1159/000354236
DO - 10.1159/000354236
M3 - Article
C2 - 24008943
AN - SCOPUS:84885032006
SN - 0250-8095
VL - 38
SP - 233
EP - 240
JO - American Journal of Nephrology
JF - American Journal of Nephrology
IS - 3
ER -