Partial ureteral obstruction dysregulates the renal renin-angiotensin system in the fetal sheep kidney

Semih Ayan, Jonathan A. Roth, Michael R. Freeman, Samuel H. Bride, Craig A Peters

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objectives. To investigate whether partial ureteral obstruction (PUO) in the fetus induces dysregulation of the renin-angiotensin system (RAS) and of transforming growth factor-beta 1 (TGF-β1) and tissue inhibitors of metalloproteinase (TIMP1) expression. Previous studies have indicated that renal and urinary tract development depend on an intact renal RAS. Fetal urinary 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-β1 and TIMP1, leads to changes in extracellular matrix composition. Methods. Bilateral PUO was created in 4 fetal sheep. Seven animals (four obstructed 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 type 1 (AT1 receptor), angiotensin receptor type 2 (AT2 receptor), TGF-β1, and TIMP1. These messages were normalized to glyceraldehyde-3-phosphate dehydrogenase 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 receptor, TGF-β1, and TIMP1 mRNA was significant in the PUO group compared with the control group (P <0.05). AT2 receptor levels did not increase, but the AT1/AT2 mRNA ratio was significantly increased over normal (P <0.005). Also, a significant linear correlation was found between the increased renal weight and increased TGF-β1 mRNA levels (P <0.005). Conclusions. Our findings suggest that fetal PUO can cause upregulation of the renal RAS and increased expression of TGF-β1 and TIMP1, which may alter the balance between the generation and degradation of the extracellular matrix. The coordinate increases in renin, angiotensinogen, and AT1 receptor mRNA levels in chronic fetal PUO may represent a maladaptive response that contributes to interstitial fibrosis and prolonged vasoconstriction. RAS components and growth factors, particularly TGF-β1, may be considered relevant targets in the prevention and treatment of congenital obstructive nephropathy.

Original languageEnglish (US)
Pages (from-to)301-306
Number of pages6
JournalUrology
Volume58
Issue number2
DOIs
StatePublished - Aug 20 2001

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Ureteral Obstruction
Renin-Angiotensin System
Sheep
Transforming Growth Factor beta
Kidney
Angiotensinogen
Messenger RNA
Renin
Angiotensin Type 2 Receptor
Angiotensin Type 1 Receptor
Extracellular Matrix
Weights and Measures
Glyceraldehyde-3-Phosphate Dehydrogenases
Tissue Inhibitor of Metalloproteinase-1
Hydronephrosis
Vasoconstriction
Reverse Transcriptase Polymerase Chain Reaction
Urinary Tract
Intercellular Signaling Peptides and Proteins
Fetus

ASJC Scopus subject areas

  • Urology

Cite this

Partial ureteral obstruction dysregulates the renal renin-angiotensin system in the fetal sheep kidney. / Ayan, Semih; Roth, Jonathan A.; Freeman, Michael R.; Bride, Samuel H.; Peters, Craig A.

In: Urology, Vol. 58, No. 2, 20.08.2001, p. 301-306.

Research output: Contribution to journalArticle

Ayan, Semih ; Roth, Jonathan A. ; Freeman, Michael R. ; Bride, Samuel H. ; Peters, Craig A. / Partial ureteral obstruction dysregulates the renal renin-angiotensin system in the fetal sheep kidney. In: Urology. 2001 ; Vol. 58, No. 2. pp. 301-306.
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abstract = "Objectives. To investigate whether partial ureteral obstruction (PUO) in the fetus induces dysregulation of the renin-angiotensin system (RAS) and of transforming growth factor-beta 1 (TGF-β1) and tissue inhibitors of metalloproteinase (TIMP1) expression. Previous studies have indicated that renal and urinary tract development depend on an intact renal RAS. Fetal urinary 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-β1 and TIMP1, leads to changes in extracellular matrix composition. Methods. Bilateral PUO was created in 4 fetal sheep. Seven animals (four obstructed 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 type 1 (AT1 receptor), angiotensin receptor type 2 (AT2 receptor), TGF-β1, and TIMP1. These messages were normalized to glyceraldehyde-3-phosphate dehydrogenase 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 receptor, TGF-β1, and TIMP1 mRNA was significant in the PUO group compared with the control group (P <0.05). AT2 receptor levels did not increase, but the AT1/AT2 mRNA ratio was significantly increased over normal (P <0.005). Also, a significant linear correlation was found between the increased renal weight and increased TGF-β1 mRNA levels (P <0.005). Conclusions. Our findings suggest that fetal PUO can cause upregulation of the renal RAS and increased expression of TGF-β1 and TIMP1, which may alter the balance between the generation and degradation of the extracellular matrix. The coordinate increases in renin, angiotensinogen, and AT1 receptor mRNA levels in chronic fetal PUO may represent a maladaptive response that contributes to interstitial fibrosis and prolonged vasoconstriction. RAS components and growth factors, particularly TGF-β1, may be considered relevant targets in the prevention and treatment of congenital obstructive nephropathy.",
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AU - Roth, Jonathan A.

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AU - Bride, Samuel H.

AU - Peters, Craig A

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N2 - Objectives. To investigate whether partial ureteral obstruction (PUO) in the fetus induces dysregulation of the renin-angiotensin system (RAS) and of transforming growth factor-beta 1 (TGF-β1) and tissue inhibitors of metalloproteinase (TIMP1) expression. Previous studies have indicated that renal and urinary tract development depend on an intact renal RAS. Fetal urinary 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-β1 and TIMP1, leads to changes in extracellular matrix composition. Methods. Bilateral PUO was created in 4 fetal sheep. Seven animals (four obstructed 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 type 1 (AT1 receptor), angiotensin receptor type 2 (AT2 receptor), TGF-β1, and TIMP1. These messages were normalized to glyceraldehyde-3-phosphate dehydrogenase 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 receptor, TGF-β1, and TIMP1 mRNA was significant in the PUO group compared with the control group (P <0.05). AT2 receptor levels did not increase, but the AT1/AT2 mRNA ratio was significantly increased over normal (P <0.005). Also, a significant linear correlation was found between the increased renal weight and increased TGF-β1 mRNA levels (P <0.005). Conclusions. Our findings suggest that fetal PUO can cause upregulation of the renal RAS and increased expression of TGF-β1 and TIMP1, which may alter the balance between the generation and degradation of the extracellular matrix. The coordinate increases in renin, angiotensinogen, and AT1 receptor mRNA levels in chronic fetal PUO may represent a maladaptive response that contributes to interstitial fibrosis and prolonged vasoconstriction. RAS components and growth factors, particularly TGF-β1, may be considered relevant targets in the prevention and treatment of congenital obstructive nephropathy.

AB - Objectives. To investigate whether partial ureteral obstruction (PUO) in the fetus induces dysregulation of the renin-angiotensin system (RAS) and of transforming growth factor-beta 1 (TGF-β1) and tissue inhibitors of metalloproteinase (TIMP1) expression. Previous studies have indicated that renal and urinary tract development depend on an intact renal RAS. Fetal urinary 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-β1 and TIMP1, leads to changes in extracellular matrix composition. Methods. Bilateral PUO was created in 4 fetal sheep. Seven animals (four obstructed 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 type 1 (AT1 receptor), angiotensin receptor type 2 (AT2 receptor), TGF-β1, and TIMP1. These messages were normalized to glyceraldehyde-3-phosphate dehydrogenase 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 receptor, TGF-β1, and TIMP1 mRNA was significant in the PUO group compared with the control group (P <0.05). AT2 receptor levels did not increase, but the AT1/AT2 mRNA ratio was significantly increased over normal (P <0.005). Also, a significant linear correlation was found between the increased renal weight and increased TGF-β1 mRNA levels (P <0.005). Conclusions. Our findings suggest that fetal PUO can cause upregulation of the renal RAS and increased expression of TGF-β1 and TIMP1, which may alter the balance between the generation and degradation of the extracellular matrix. The coordinate increases in renin, angiotensinogen, and AT1 receptor mRNA levels in chronic fetal PUO may represent a maladaptive response that contributes to interstitial fibrosis and prolonged vasoconstriction. RAS components and growth factors, particularly TGF-β1, may be considered relevant targets in the prevention and treatment of congenital obstructive nephropathy.

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