Amelioration of angiotensin II-induced salt-sensitive hypertension by liver-type fatty acid-binding protein in proximal tubules.
Inappropriate activation of the intrarenal renin-angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid-binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid-binding protein on post-angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid-binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II-induced SSHT. Overexpression of tubular liver-type fatty acid-binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin-angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid-binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid-binding protein, and found that gene transfection of liver-type fatty acid-binding protein and, in part, recombinant liver-type fatty acid-binding protein administration had significantly attenuated angiotensin II-induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid-binding protein in the proximal tubules may protect against angiotensin II-induced SSHT by attenuating activation of the intrarenal renin-angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid-binding protein in the proximal tubules may be a novel therapeutic target for SSHT.
Division of Nephrology, Department of Internal Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. yasu@juntendo.ac.jp.
Ken
K
Osaki
Yusuke
Y
Suzuki
Takeshi
T
Sugaya
Chiaki
C
Tanifuji
Akira
A
Nishiyama
Satoshi
S
Horikoshi
Yasuhiko
Y
Tomino
D000804:Angiotensin II; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology
C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D017382:Reactive Oxygen Species; D000808:Angiotensinogen; D000804:Angiotensin II
kidney tubules, proximal; liver fatty acid–binding protein; oxidative stress; renin–angiotensin system