Renal renin-angiotensin system dysregulation caused by partial bladder outlet obstruction in fetal sheep

Background To determine whether fetal renal obstruction activates the renal renin-angiotensin system (RAS), an important mediator in normal kidney dev elopment and obstructive nephropathy, we used a model of fetal partial blad der outlet obstruction (PBOO). Methods. Total RNA and protein was extracted from kidney of sheep fetuses w ith 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 s heep at various lime points between 60 and 135 days of gestation (total N = 19). Relative levels of mRNA for renin, angiotensinogen, type 1 and 2 angi otensin II (Ang II) receptors (AT-1 and AT-2), and transforming growth fact or-beta 1 (TGF-beta 1) were assessed by semiquantitative reverse transcript ion-polymerase chain reaction. Expression levels of AT-2 receptor protein w ere measured by Western blot analysis. Results. Renin mRNA expression was increased (250%) after two weeks of obst ruction. In normal fetuses, AT-1 expression was low at 60 to 75 days of ges tation and increased toward the end of gestation, whereas AT-2 expression s howed a reversed pattern. At 109 days, PBOO caused an increased expression of AT-2 mRNA compared with normals (400%). Correspond ingly, AT-2 receptor protein was more abundant in obstructed kidneys. TGF-B1 mRNA expression was significantly increased in obstructed kidneys at 109 days gestation. Conclusions. These observations confirm the reciprocal developmental regula tion of AT-1 and AT-2 receptors' expression, suggesting their functional ro le in renal development. Partial bladder outlet obstruction produces specif ic alterations: increased renin expression and altered balance of receptor subtypes, which may induce altered functional and vascular regulation of th e obstructed fetal kidney. TGF-beta 1, a mediator of Ang II-induced fibrosi s, may play a role in inducing and propagating interstitial fibrosis.