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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Rys-Sikora, Krystyna E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Houston
Schools of Pharmacy
United States
Zip Code
Patel, Sanket N; Narayan, Prakash; Goldberg, Itzhak D et al. (2018) Kidney Appreciates Stable Blood Pressure. Am J Hypertens 31:532-533
Patel, Sanket; Hussain, Tahir (2018) Role of AT2R (Angiotensin Type 2 Receptor) in Maintaining Sodium-Potassium Balance. Hypertension 71:563-565
Patel, Sanket N; Ali, Quaisar; Samuel, Preethi et al. (2017) Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney. Hypertension 70:831-838
Ali, Quaisar; Dhande, Isha; Samuel, Preethi et al. (2016) Angiotensin type 2 receptor null mice express reduced levels of renal angiotensin II type 2 receptor/angiotensin (1-7)/Mas receptor and exhibit greater high-fat diet-induced kidney injury. J Renin Angiotensin Aldosterone Syst 17:
Patel, Sanket N; Ali, Quaisar; Hussain, Tahir (2016) Angiotensin II Type 2-Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt-Fed Obese Zucker Rats. Hypertension 67:906-15
Ali, Quaisar; Patel, Sanket; Hussain, Tahir (2015) Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats. Am J Physiol Renal Physiol 308:F1379-85
Dhande, Isha; Ma, Wanshu; Hussain, Tahir (2015) Angiotensin AT2 receptor stimulation is anti-inflammatory in lipopolysaccharide-activated THP-1 macrophages via increased interleukin-10 production. Hypertens Res 38:21-9
Nag, Sourashish; Khan, Mohammad Azhar; Samuel, Preethi et al. (2015) Chronic angiotensin AT2R activation prevents high-fat diet-induced adiposity and obesity in female mice independent of estrogen. Metabolism 64:814-25
Ali, Quaisar; Wu, Yonnie; Nag, Sourashish et al. (2014) Estimation of angiotensin peptides in biological samples by LC/MS method. Anal Methods 6:215-222
Samuel, Preethi; Khan, Mohammad Azhar; Nag, Sourashish et al. (2013) Angiotensin AT(2) receptor contributes towards gender bias in weight gain. PLoS One 8:e48425

Showing the most recent 10 out of 29 publications