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| DIFFERENTIAL REGULATION OF ANGIOTENSIN-II AND LOSARTAN BINDING-SITES IN GLOMERULI AND MESANGIAL CELLS |
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| Author(s): CHANSEL D, BIZET T, VANDERMEERSCH S, PHAM P, LEVY B, ARDAILLOU R |
| Source: AMERICAN JOURNAL OF PHYSIOLOGY Volume: 266 Issue: 3 Pages: F384-F393 Part: Part 2 Published: MAR 1994 |
| Times Cited: 21 References: 34 |
| Abstract: The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using I-125-[Sar(1),Ala(8)]ANG II and [H-3]losartan as radiolabeled ligand, respectively. ANG II receptors were downregulated in glomeruli from rats infused with ANG II during 3 wk or rats receiving losartan orally during 1 wk. The number of sites (B-max) was reduced, but the dissociation constant (K-d) value was unchanged. Losartan receptors were downregulated in glomeruli from rats receiving losartan, but remained unchanged in glomeruli from rats infused with ANG II. Since in vivo administration of losartan results in increase of plasma ANG II and formation of metabolites, in vitro studies using human mesangial cells were performed to better analyze the present findings. Treatment of mesangial cells during 4 days by ANG II, losartan, or its metabolite, EXP-3174, also produced downregulation of I-125-[Sar(1),Ala(8)]ANG II binding sites with a decreased B-max and unchanged K-d value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [H-3]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [H-3]losartan binding sites. Under all conditions, only B-max was modified. Whereas internalization of [H-3]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized I-125-[Sar(1),Ala(8)]ANG II after exposure of the cells to ANG II or AT(1) antagonists. No change was observed in mesangial cell ATL receptor mRNA levels. This study demonstrates that 1) AT(1) mRNA is expressed in human mesangial cells; 2) the characteristics of I-125-[Sar(1),Ala(8)]ANG II and [H-3]losartan binding sites in rat glomeruli and human mesangial cells are different, with K-d and B-max values greater in both preparations when [H-3]losartan was utilized; 3) both types of binding sites obey different regulations, and the effects of losartan in vivo are due in part to the associated increase in plasma ANG II levels and the transformation of the drug into its metabolite, EXP-3174; 4) downnregulation of AT(1) receptors does not depend on changes in mRNA expression but is associated with increased relative internalization. |
| Document Type: Article |
| Language: English |
Addresses:
1. HOP TENON, INSERM, U64, F-75020 PARIS, FRANCE
2. HOP LARIBOISIERE, INSERM, U141, F-75020 PARIS, FRANCE
3. CENS, DEPT BIOL, F-91190 GIF SUR YVETTE, FRANCE |
| Publisher: AMER PHYSIOLOGICAL SOC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Physiology |
| IDS Number: NF861 |
| ISSN: 0002-9513 |
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