Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation.

Niimura, Fumio; Labosky, Patricia A.; Kakuchi, Junji; Okubo, Soichiro; Yoshida, Hiroaki; Oikawa, Tsuyoshi; Ichiki, Toshihiro; Naftilan, Allen J.; Fogo, Agnes B.; Inagami, Tadashi

doi:10.1172/jci118366

Cited by 319 publications

(246 citation statements)

References 38 publications

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“…The abnormalities present in the homozygous mutant ACE.2 mice are similar to those described for mice completely lacking ACE and for mice that lack angiotensinogen, the precursor to angiotensin II (16,17,23,24). This suggests that the ACE.2 homozygous mutant mice cannot generate sufficient angiotensin II despite significant plasma ACE activity; a finding consistent with research indicating that the bulk of angiotensin II formation occurs in the tissues such as the lung (11).…”

Section: Discussionsupporting

confidence: 76%

“…It has previously been reported that mice completely lacking ACE develop renal lesions that involve blunting of the renal papilla and associated dilatation of the renal calyces (17). These lesions are almost certainly due to lack of angiotensin II production since they also occur in mice that lack angiotensinogen and in rats treated neonatally with AT 1 receptor antagonists (23,24,26). It is not clear whether the renal abnormalities are due directly to a requirement for angiotensin II in normal renal development, or if they are secondary to the low blood pressure or increased urine flow present in these animals.…”

Section: Discussionmentioning

confidence: 99%

“…This cDNA fragment was generated by PCR from cloned ACE cDNA with the primers 5 Ј -CAGAACGCGTGCAGACCTA-GAGACTGATGAAGC-3 Ј and 5 Ј -CAGACGATATCGACCTT-TAATTGTATTCACAG-3 Ј . The fragment incorporates 2.2 kb of ACE cDNA sequence including all of the somatic ACE coding exons (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) downstream of the neomycin cassette in the previous construct and 216 bp of 3 Ј untranslated region including a poly-adenylation site. The cDNA fragment contains a consensus 3 Ј splice acceptor sequence (GCAG) immediately 5 Ј of the coding region.…”

Section: Creation Of Mice With a Mutant Ace Allelementioning

confidence: 99%

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The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Esther¹,

Marino²,

Howard³

et al. 1997

J. Clin. Invest.

263

210

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Angiotensin-converting enzyme (ACE) generates the vasoconstrictor angiotensin II, which plays a critical role in maintenance of blood pressure in mammals. Although significant ACE activity is found in plasma, the majority of the enzyme is bound to tissues such as the vascular endothelium. We used targeted homologous recombination to create mice expressing a form of ACE that lacks the COOH-terminal half of the molecule. This modified ACE protein is catalytically active but entirely secreted from cells. Mice that express only this modified ACE have significant plasma ACE activity but no tissue-bound enzyme. These animals have low blood pressure, renal vascular thickening, and a urine concentrating defect. The phenotype is very similar to that of completely ACE-deficient mice previously reported, except that the renal pathology is less severe. These studies strongly support the concept that the tissue-bound ACE is essential to the control of blood pressure and the structure and function of the kidney. ( J. Clin. Invest. 1997. 99:2375-2385.)

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Creation Of Mice With a Mutant Ace Allelementioning

confidence: 99%

See 1 more Smart Citation

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Esther¹,

Marino²,

Howard³

et al. 1997

J. Clin. Invest.

263

210

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“…Another phenotype observed in the Ren1cϪ/Ϫ mice is medial thickening of the small arteries in the kidney but not of the vessels outside the kidney. This phenotype has been described by others in renin-deficient mice (5) as well as in mice deficient of Agt (15,17,28), Ace (18,19), Agtr1a (29), and Agtr1a/1b (20,21). Mononuclear cell infiltration surrounding the thickened arteries is evident, suggesting that some common pathogenic mechanism causes vascular thickening and perivascular inflammation.…”

Section: Discussionsupporting

confidence: 65%

Ren1c Homozygous Null Mice Are Hypotensive and Polyuric, but Heterozygotes Are Indistinguishable from Wild-Type

Takahashi¹,

López²,

Cowhig³

et al. 2005

Journal of the American Society of Nephrology

132

135

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“…Six-micrometer sections were stained for renin using a previously characterized polyclonal goat anti-rat renin antibody 24 (a gift from Dr Tadashi Inagami at the Vanderbilt University), avidinbiotin-peroxidase (Vectastain ABC kit; Vector Laboratories, Burlingame, Calif), and methods described previously. 25 Negative controls included omission of primary and secondary antibodies.…”

Section: Renin Immunohistochemistrymentioning

confidence: 99%

Angiotensin Subtype-2 Receptors Inhibit Renin Biosynthesis and Angiotensin II Formation

et al. 2005

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Abstract-Renin is regulated by angiotensin subtype 1 (AT 1 ) receptor, but it is unknown whether angiotensin subtype 2 (AT 2 ) receptor contributes to this regulation. We hypothesized that AT 2 receptors inhibit angiotensin II (Ang II) through inhibition of renin biosynthesis. We monitored changes in renal Ang II, renin mRNA and protein expression, and plasma renin concentration (PRC) in response to renal cortical administration of the AT 1 receptor blocker valsartan or the AT 2 receptor blocker PD 123319 (PD) in conscious rats administered low sodium intake (LS (Ang II) is the major effector hormone of the renin-angiotensin system (RAS). Most of the known physiological functions and pathologic effects associated with Ang II are mediated by the angiotensin subtype 1 (AT 1 ) receptor, including renin inhibition. 1 In contrast, the functions of the angiotensin subtype 2 (AT 2 ) receptor are still being elucidated. The AT 2 receptor is expressed abundantly during fetal development and declines after birth. [1][2][3] In mammalian adults, the AT 2 receptor had been reported in multiple organs, including the kidney. 4 -6 Currently, the AT 2 receptor has several described functions related to inhibition of cell growth, promotion of cell differentiation, and stimulation of apoptosis. [7][8][9][10][11][12] Previously, we demonstrated that during sodium depletion, the AT 2 receptor mediates renal production of bradykinin, nitric oxide (NO), and cGMP. [13][14][15][16][17] Unlike the well-known effect of AT 1 receptor on renin production, 18 -19 the influence of the AT 2 receptor on renal renin biosynthesis and Ang II production is not known.In this study, we tested the hypothesis that the AT 2 receptor inhibits renal renin synthesis and Ang II production. We used multiple techniques including renal interstitial microdialysis, [13][14][15][16][17] real-time quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and enzymelinked immunoassays for monitoring changes in renal Ang II, renin mRNA, renin protein expression, and plasma renin concentration to investigate whether intrarenal AT 2 receptors regulate renin production and Ang II formation. We monitored renal interstitial levels of Ang II in conscious rats during sodium restriction, a condition known to increase AT 2 receptor expression, and during AT 1 and AT 2 receptor blockade. 5 A distinct advantage of the microdialysis technique 13 is the ability to monitor renal Ang II levels in conscious rats without undesirable hemodynamic changes. In this study, we demonstrate for the first time to our knowledge that AT 2 receptors regulate the activity of the RAS through inhibition of renin biosynthesis in young rats. Methods Renal Microdialysis TechniqueFor the determination of renal interstitial fluid (RIF) Ang II, we constructed a microdialysis probe as previously described. [13][14][15][16][17] In vitro, best recovery for Ang II was observed with a perfusion rate of 3 L/min, and was Ϸ53%. Animal PreparationThe experiments were approved by the U...

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Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation.

Cited by 319 publications

References 38 publications

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Ren1c Homozygous Null Mice Are Hypotensive and Polyuric, but Heterozygotes Are Indistinguishable from Wild-Type

Angiotensin Subtype-2 Receptors Inhibit Renin Biosynthesis and Angiotensin II Formation

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