Angiotensin Type 1 Receptor Resistance To Blockade In The Opossum Proximal Tubule Cell Due To Variations In The Binding Pocket.

Angiotensin Type 1 Receptor Resistance To Blockade In The Opossum Proximal Tubule Cell Due To Variations In The Binding Pocket. Am J Physiol Renal Physiol. 2013 Feb 6; Authors: Nistala R, Andresen BT, Pulakat L, Meuth A, Sinak C, Mandavia C, Thekkumkara T, Speth RC, Whaley-Connell AT, Sowers JR Abstract 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, bind 125I-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, non-radioactive Ang II competes 125I-Ang II efficiently, while a ten-fold molar excess of olmesartan and the AT2R blocker PD123319 are unable to bl...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research