Angiostatin production increases in response to decreased nitric oxide in aging rat kidney

The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin...

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Published in:Laboratory investigation 2013-03, Vol.93 (3), p.334-343
Main Authors: Satoh, Minoru, Kidokoro, Kengo, Ozeki, Masahito, Nagasu, Hajime, Nishi, Yuko, Ihoriya, Chieko, Fujimoto, Sohachi, Sasaki, Tamaki, Kashihara, Naoki
Format: Article
Language:English
Subjects:
Aging - metabolism
Angiostatins - biosynthesis
Animals
Blotting, Western
Cathepsin D - metabolism
Human Umbilical Vein Endothelial Cells
Humans
Immunohistochemistry
Kidney - metabolism
Molsidomine
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide - metabolism
Rats
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Statistics, Nonparametric
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Summary:The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin is a kringle-containing fragment of plasminogen and is a potent inhibitor of angiogenesis in vivo. Whether angiostatin generation is increased in the aging kidney has not been investigated. We examined 4, 10, 16, and 24-month-old Sprague-Dawley rats for angiostatin production and found that angiostatin generation was increased in aged rats. The protein expression and the activity of cathepsin D-the enzyme for angiostatin production--were increased in aged rats. In the aging kidney, nitric oxide (NO) availability is decreased. To investigate the role of NO in angiostatin production, human umbilical vein endothelial cells were treated with L-NG-nitroarginine methyl ester (L-NAME). L-NAME-treated cells showed increased cathepsin D activity and angiostatin production. For in vivo experiments, 16- to 18-month-old rats were treated with L-NAME or molsidomine for 3 months. Angiostatin production was increased in L-NAME-treated kidney, accompanied by increased cathepsin D activity. In contrast, angiostatin production was decreased in molsidomine-treated kidney, accompanied by decreased cathepsin D activity. In conclusion, angiostatin generation by cathepsin D was increased in the aging rat kidney. Decreased NO production activated cathepsin D activity. Increased angiostatin production may be related to capillary loss and interstitial damage in the aging rat kidney.
ISSN:0023-6837
1530-0307
DOI:10.1038/labinvest.2012.171