| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
In order to clarify the functional importance of the angiotensinogen of kidney origin, we inactivated the mouse angiotensinogen gene in a tissue-specific manner, and investigated whether water and sodium balance would be maintained in the absence of the production of angiotensinogen in the kidney. First, we generated a mouse strain in which two loxP fragments were inserted into the mouse angiotensinogen gene. In this mouse, the angiotensinogen gene is inactivated only where Cre recombinase is produced. Second, we generated a transgenic mouse strain (KAP-Cre mouse) in which Cre recombinase is expressed in the kidney proximal straight tubules. Then, by crossing these two mouse strains, we obtained mice with the genotype of [Agt^<loxP>/Agt^<loxP>,KAP-Cre(+)]. In the male mice with this genotype, angiotensinogen mRNA was reduced in the kidney but not in the liver, showing that angiotensinogen is inactivated only in the kidney proximal straight tubules. We also generated the mice in which a
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ngiotensinogen gene is inactivated only in the liver, by using Albumin-Cre mouse instead of KAP-Cre mouse. In addition, the mice in which AT 1a gene is inactivated only in the proximal straight tubules were generated.
Kidney-specific angiotensinogen deficient mice and proximal straight tubule-specific AT1a deficient mice showed comparable blood pressure to the control mice. These mice tolerated sodium restriction fairly well, with diminished urine volume and sodium excretion. In contrast, liver-specific angiotensinogen deficient mice were hypotensive and polyuric, with sustained sodium excretion even under sodium restriction. These results suggested that angiotensinogen of kidney origin was of limited importance for sodium/water preservation.
These three kinds of mice were subjected to UUO, a model of renal interstitial fibrosis. Preliminary observation showed somewhat exaggerated fibrosis in the kidney-specific angiotensinogen deficient mice. Further investigation is required to elucidate the functional role for angiotensinogen of kidney origin in the process of renal interstitial fibrosis. Less
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