Angiotensin type 1 receptor resistance to blockade in the opossum proximal tubule cell due to variations in the binding pocket
| Autor: | James R. Sowers, Catherine Sinak, Alex Meuth, Thomas J. Thekkumkara, Robert C. Speth, Bradley T. Andresen, Ravi Nistala, Lakshmi Pulakat, Chirag Mandavia, Adam Whaley-Connell |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Physiology Drug Resistance Tetrazoles urologic and male genital diseases Protein Structure Secondary Receptor Angiotensin Type 1 Cell Line Iodine Radioisotopes Kidney Tubules Proximal Species Specificity Opossum Internal medicine Renin–angiotensin system medicine Animals Humans Vasoconstrictor Agents RNA Messenger Binding site Receptor Phylogeny Janus kinase 2 Binding Sites Polymorphism Genetic biology Angiotensin II Imidazoles Articles Opossums Janus Kinase 2 biology.organism_classification Protein Structure Tertiary Rats Endocrinology biology.protein Phosphorylation Olmesartan Angiotensin II Type 1 Receptor Blockers hormones hormone substitutes and hormone antagonists medicine.drug |
| Popis: | Blockade of the angiotensin (ANG) II receptor type 1 (AT1R) with angiotensin receptor blockers (ARBs) is widely used in the treatment of hypertension. However, ARBs are variably effective in reducing blood pressure, likely due, in part, to polymorphisms in the ARB binding pocket of the AT1R. Therefore, we need a better understanding of variations/polymorphisms that alter binding of ARBs in heterogeneous patient populations. The opossum proximal tubule cell (OKP) line is commonly used in research to evaluate renal sodium handling and therefore blood pressure. Investigating this issue, we found natural sequence variations in the opossum AT1R paralleling those observed in the human AT1R. Therefore, we posited that these sequence variations may explain ARB resistance. We demonstrate that OKP cells express AT1R mRNA, bind125I-labeled ANG II, and exhibit ANG II-induced phosphorylation of Jak2. However, Jak2 phosphorylation is not inhibited by five different ARBs commonly used to treat hypertension. Additionally, nonradioactive ANG II competes125I-ANG II efficiently, whereas a 10-fold molar excess of olmesartan and the ANG II receptor type 2 blocker PD-123319 is unable to block125I-ANG II binding. In contrast, ANG II binding to OKP cells stably expressing rat AT1ARs, which have a conserved AT1R-binding pocket with human AT1R, is efficiently inhibited by olmesartan. A novel observation was that resistance to ARB binding to opossum AT1Rs correlates with variations from the human receptor at positions 108, 163, 192, and 198 within the ARB-binding pocket. These observations highlight the potential utility of evaluating AT1R polymorphisms within the ARB-binding pocket in various hypertensive populations. |
| Databáze: | OpenAIRE |
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