title: Renal renin-angiotensin system dysregulation caused by partial bladder outlet obstruction in fetal sheep.
abstract: BACKGROUND
  To determine whether fetal renal obstruction activates the renal renin-angiotensin system (RAS), an important mediator in normal kidney development and obstructive nephropathy, we used a model of fetal partial bladder outlet obstruction (PBOO).
  
  
  METHODS
  Total RNA and protein was extracted from kidney of sheep fetuses with partial bladder outlet obstruction created at 95 days gestation, after 2 (N = 6) and 5 weeks of obstruction (term; N = 6), and from normal fetal sheep at various time points between 60 and 135 days of gestation (total N = 19). Relative levels of mRNA for renin, angiotensinogen, type 1 and 2 angiotensin II (Ang II) receptors (AT-1 and AT-2), and transforming growth factor-beta1 (TGF-beta1) were assessed by semiquantitative reverse transcription-polymerase chain reaction. Expression levels of AT-2 receptor protein were measured by Western blot analysis.
  
  
  RESULTS
  Renin mRNA expression was increased (250%) after two weeks of obstruction. In normal fetuses, AT-1 expression was low at 60 to 75 days of gestation and increased toward the end of gestation, whereas AT-2 expression showed a reversed pattern. At 109 days, PBOO caused an increased expression of AT-2 mRNA compared with normals (400%). Correspondingly, AT-2 receptor protein was more abundant in obstructed kidneys. TGF-beta1 mRNA expression was significantly increased in obstructed kidneys at 109 days gestation.
  
  
  CONCLUSIONS
  These observations confirm the reciprocal developmental regulation of AT-1 and AT-2 receptors' expression, suggesting their functional role in renal development. Partial bladder outlet obstruction produces specific alterations: increased renin expression and altered balance of receptor subtypes, which may induce altered functional and vascular regulation of the obstructed fetal kidney. TGF-beta1, a mediator of Ang II-induced fibrosis, may play a role in inducing and propagating interstitial fibrosis.
authors.affiliation: Department of Urology, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gobet
authors.forename: J M
authors.initials: JM
authors.lastname: Park
authors.forename: H T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: B
authors.initials: B
authors.lastname: Chang
authors.forename: L J
authors.initials: LJ
authors.lastname: Cisek
authors.forename: C A
authors.initials: CA
authors.lastname: Peters
mesh_terms: D000818:Animals; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D016212:Transforming Growth Factor beta / Q000235:genetics; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*
chemical_list: D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D012083:Renin