Role of asymmetrical dimethylarginine in renal microvascular endothelial dysfunction in chronic renal failure with hypertension.
We examined whether endothelial function of the renal microcirculation was impaired in a model of chronic renal failure (CRF), and further assessed the role of asymmetrical dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of acetylcholine (0.01 microg/kg/min) elicited 22+/-2% and 20+/-2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12+/-2%; efferent, 11+/-1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of homocysteine (12.2+/-0.7 vs. 6.8+/-0.4 micromol/l) and ADMA were elevated (2.60+/-0.13 vs. 1.50+/-0.08 micromol/l). The inhibition of S-adenosylmethionine-dependent protein arginine N-methyltransferase by adenosine dialdehyde decreased plasma ADMA levels, and improved the acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute methionine loading impaired the acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.
Okubo
Ken
K
Department of Internal Medicine, School of Medicine, Keio University. Tokyo, Japan. ; *Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hayashi
Koichi
K
Wakino
Shu
S
Matsuda
Hiroto
H
Kubota
Eiji
E
Honda
Masanori
M
Tokuyama
Hirobumi
H
Yamamoto
Tokunori
T
Kajiya
Fumihiko
F
Saruta
Takao
T
D000109:Acetylcholine / Q000494:pharmacology; D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D004285:Dogs; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D016133:Polymerase Chain Reaction
C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D000109:Acetylcholine