title: Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor-deficient mice.
abstract: Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-beta by Northern blot analysis. Nuclear factor-kappaB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-beta was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-kappaB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamasaki
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Maeshima
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.affiliation: Institute of Applied Biochemistry, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaragi, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Department of Medicine III, Okayama University Medical School, Okayama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D003094:Collagen / Q000032:analysis; D005260:Female; D005355:Fibrosis; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014517:Ureteral Obstruction / Q000473:pathology*
chemical_list: D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D003094:Collagen