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Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells.
Am J Physiol. 1994 Mar; 266(3 Pt 2):F384-93.AJ

Abstract

The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using 125I-[Sar1,Ala8]ANG II and [3H]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 (Bmax) was reduced, but the dissociation constant (Kd) 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 125I-[Sar1,Ala8]ANG II binding sites with a decreased Bmax and unchanged Kd value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [3H]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [3H]losartan binding sites. Under all conditions, only Bmax was modified. Whereas internalization of [3H]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized 125I-[Sar1,Ala8]ANG II after exposure of the cells to ANG II or AT1 antagonists. No change was observed in mesangial cell AT1 receptor mRNA levels. This study demonstrates that 1) AT1 mRNA is expressed in human mesangial cells; 2) the characteristics of 125I-[Sar1,Ala8]ANG II and [3H]losartan binding sites in rat glomeruli and human mesangial cells are different, with Kd and Bmax values greater in both preparations when [3H]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) downregulation of AT1 receptors does not depend on changes in mRNA expression but is associated with increased relative internalization.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale (INSERM) 64, Hôpital Tenon, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8160786

Citation

Chansel, D, et al. "Differential Regulation of Angiotensin II and Losartan Binding Sites in Glomeruli and Mesangial Cells." The American Journal of Physiology, vol. 266, no. 3 Pt 2, 1994, pp. F384-93.
Chansel D, Bizet T, Vandermeersch S, et al. Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells. Am J Physiol. 1994;266(3 Pt 2):F384-93.
Chansel, D., Bizet, T., Vandermeersch, S., Pham, P., Levy, B., & Ardaillou, R. (1994). Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells. The American Journal of Physiology, 266(3 Pt 2), F384-93.
Chansel D, et al. Differential Regulation of Angiotensin II and Losartan Binding Sites in Glomeruli and Mesangial Cells. Am J Physiol. 1994;266(3 Pt 2):F384-93. PubMed PMID: 8160786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells. AU - Chansel,D, AU - Bizet,T, AU - Vandermeersch,S, AU - Pham,P, AU - Levy,B, AU - Ardaillou,R, PY - 1994/3/1/pubmed PY - 1994/3/1/medline PY - 1994/3/1/entrez SP - F384 EP - 93 JF - The American journal of physiology JO - Am. J. Physiol. VL - 266 IS - 3 Pt 2 N2 - The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using 125I-[Sar1,Ala8]ANG II and [3H]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 (Bmax) was reduced, but the dissociation constant (Kd) 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 125I-[Sar1,Ala8]ANG II binding sites with a decreased Bmax and unchanged Kd value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [3H]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [3H]losartan binding sites. Under all conditions, only Bmax was modified. Whereas internalization of [3H]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized 125I-[Sar1,Ala8]ANG II after exposure of the cells to ANG II or AT1 antagonists. No change was observed in mesangial cell AT1 receptor mRNA levels. This study demonstrates that 1) AT1 mRNA is expressed in human mesangial cells; 2) the characteristics of 125I-[Sar1,Ala8]ANG II and [3H]losartan binding sites in rat glomeruli and human mesangial cells are different, with Kd and Bmax values greater in both preparations when [3H]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) downregulation of AT1 receptors does not depend on changes in mRNA expression but is associated with increased relative internalization. SN - 0002-9513 UR - https://www.unboundmedicine.com/medline/citation/8160786/Differential_regulation_of_angiotensin_II_and_losartan_binding_sites_in_glomeruli_and_mesangial_cells_ L2 - http://www.physiology.org/doi/full/10.1152/ajprenal.1994.266.3.F384?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -