Recently, we have observed that blockade of AT1 receptors causes greater diuresis and natriuresis in obese than in lean Zucker rats. Additionally, in vitro experiments demonstrate an increase in the AT1 receptor number on brush border membranes and a greater stimulation of the proximal tubule Na/H exchanger and Na,K-ATPase activity by Ang II in obese compared to lean rats. Furthermore, pretreatment of proximal tubule epithelial cells (OK cells) with insulin caused a potentiation of the Ang II-mediated stimulation of Na/K-ATPase and Na/H-exchanger and an increase in AT1 receptor expression. Collectively, these results lead us to hypothesize that Ang II increases tubular sodium and water reabsorption and contributes to hypertension in obese Zucker rats via an enhanced AT1 receptor signaling due to AT1 receptor up-regulation; and that the AT1 receptor up-regulation is caused by hyperinsulinemia, a characteristic of obese Zucker rats. To test this hypothesis we will quantify the AT1 receptor expression on proximal tubule plasma membranes using ligand binding, AT1mRNA contents/rate of transcription in proximal tubules, and examine the AT1 receptor signaling in lean and obese rats. To understand the role of hyperinsulinemia on the AT1 receptor up-regulation, obese rats will be treated with rosiglitazone/streptozotocin to lower the levels of plasma insulin or lean rats will be treated with exogenous insulin to produce hyperinsulinemia. The AT1 receptor number, signaling and function on sodium reabsorption will be studied in these treated rats. The exaggerated natriuretic response following AT1 receptor blockade in obese rats could also indicate exaggerated AT2 receptor signaling. Therefore, additional experiments are designed to determine the role of AT2 receptors on sodium excretion and determine the abundance of AT2 receptors. The proposed study will provide the molecular mechanism of AT1 receptor up-regulation and the enhanced AT1 receptor signaling. From a therapeutic perspective, it will also allow us to establish whether lowering of the plasma insulin levels leads to the restoration of the AT1 receptors function to normal levels and reduces blood pressure in obese rats.
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