S. Ayan et al., Partial ureteral obstruction dysregulates the renal renin-angiotensin system in the fetal sheep kidney, UROLOGY, 58(2), 2001, pp. 301-306
Objectives. To investigate whether partial ureteral obstruction (PUO) in th
e fetus induces dysregulation of the renin-angiotensin system (RAS) and of
transforming growth factor-beta 1 (TGF-beta1) and tissue inhibitors of meta
lloproteinase (TIMP1) expression. Previous studies have indicated that rena
l and urinary tract development depend on an intact renal RAS. Fetal urinar
y obstruction is distinct from postnatal obstruction. It has been suggested
in postnatal animal studies that dysregulation of the RAS, and subsequent
increased expression of TGF-beta1 and TIMP1, leads to changes in extracellu
lar matrix composition.
Methods. Bilateral PUO was created in 4 fetal sheep. Seven animals (four ob
structed and three controls) were killed at birth and their kidneys removed
. Semiquantitative reverse transcriptase-polymerase chain reaction was used
to quantify the levels of renin, angiotensinogen, angiotensin receptor typ
e I (AT] receptor), angiotensin receptor type 2 (AT2 receptor), TGF-beta1,
and TIMP1. These messages were normalized to glyceraldehyde-3-phosphate deh
ydrogenase mRNA.
Results. All obstructed animals had moderate to severe hydronephrosis with
enlarged kidneys (mean weight 22.0 g versus 9.4 g for the control animals;
P <0.05). The increase in the levels of renin, angiotensinogen, AT1 recepto
r, TGF-<beta>1, and TIMP1 mRNA was significant in the PUO group compared wi
th the control group (P <0.05). AT2 receptor levels did not increase, but t
he AT1/AT2 mRNA ratio was significantly increased over normal (P <0.005). A
lso, a significant linear correlation was found between the increased renal
weight and increased TGF-beta1 mRNA levels (P <0.005).
Conclusions. Our findings suggest that fetal PUO can cause upregulation of
the renal RAS and increased expression of TGF-<beta>1 and TIMP1, which may
alter the balance between the generation and degradation of the extracellul
ar matrix. The coordinate increases in renin, angiotensinogen, and AT1 rece
ptor mRNA levels in chronic fetal PUO may represent a maladaptive response
that contributes to interstitial fibrosis and prolonged vasoconstriction. R
AS components and growth factors, particularly TGF-beta1, may be considered
relevant targets in the prevention and treatment of congenital obstructive
nephropathy. UROLOGY 58: 301-306, 2001. (C) 2001, Elsevier Science Inc.