title: Renoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activation.
abstract: The aim of this study was to assess the renoprotective effect of renal human liver-type fatty acid binding protein (hL-FABP) and angiotensin II (ANG II) type 1A receptor (AT1a) loss in renal injury caused by renin-angiotensin system (RAS) activation. We established hL-FABP chromosomal transgenic mice (L-FABP(+/-)AT1a(+/+)), crossed the L-FABP(+/-)AT1a(+/+) with AT1a knockdown homo mice (L-FABP(-/-)AT1a(-/-)), and generated L-FABP(+/-)AT1a hetero mice (L-FABP(+/-)AT1a(+/-)). After the back-cross of these cubs, L-FABP(+/-)AT1a(-/-) were obtained. To activate the renal RAS, wild-type mice (L-FABP(-/-)AT1a(+/+)), L-FABP(+/-)AT1a(+/+), L-FABP(-/-)AT1a(+/-), L-FABP(+/-)AT1a(+/-), L-FABP(-/-)AT1a(-/-), and L-FABP(+/-)AT1a(-/-) were administered high-dose systemic ANG II infusion plus a high-salt diet for 28 days. In the L-FABP(-/-)AT1a(+/+), RAS activation (L-FABP(-/-)AT1a(+/+)RAS) caused hypertension and tubulointerstitial damage. In the L-FABP(+/-)AT1a(+/+)RAS, tubulointerstitial damage was significantly attenuated compared with L-FABP(-/-)AT1a(+/+)RAS. In the AT1a partial knockout (AT1a(+/-)) or complete knockout (AT1a(-/-)) mice, reduction of AT1a expression led to a significantly lower degree of renal injury compared with L-FABP(-/-)AT1a(+/+)RAS or L-FABP(+/-)AT1a(+/+)RAS mice. Renal injury in L-FABP(+/-)AT1a(+/-)RAS mice was significantly attenuated compared with L-FABP(-/-)AT1a(+/-)RAS mice. In both L-FABP(-/-)AT1a(-/-)RAS and L-FABP(+/-)AT1a(-/-)RAS mice, renal damage was rarely found. The degrees of renal hL-FABP expression and urinary hL-FABP levels increased by RAS activation and gradually decreased along with reduction of AT1a expression levels. In conclusion, in this mouse model, renal hL-FABP expression and a decrease in AT1a expression attenuated tubulointerstitial damage due to RAS activation.
authors.affiliation: Nephrology and Hypertension, St. Marianna Univ. School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki 216-8511, Japan. kimura@marianna-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichikawa
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kamijo-Ikemori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Yugo
authors.initials: Y
authors.lastname: Shibagaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Kimie
authors.initials: K
authors.lastname: Katayama
authors.forename: Seiko
authors.initials: S
authors.lastname: Hoshino
authors.forename: Junko
authors.initials: J
authors.lastname: Igarashi-Migitaka
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Hirata
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000818:Animals; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D051436:Renal Insufficiency, Chronic / Q000473:pathology / Q000517:prevention & control*; D012084:Renin-Angiotensin System / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
chemical_list: D050556:Fatty Acid-Binding Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary
keywords: AT1a knockout; L-FABP; RAS activation; oxidative stress; tubulointerstitial damage