The long-term goal of this proposal is to evaluate a physiological and therapeutic role for the renal angiotensin II (Ang II) AT2 receptors in improving renal/cardiovascular function and treating hypertension associated with obesity/diabetes. Of the two Ang II receptors, AT1 is known to mediate most of the Ang II actions such as antinatriuresis and increased blood pressure (BP). The AT2 receptor is suggested to function as an antagonist of AT1 receptors;however, low expression of the AT2 receptor has hindered development of a clear understanding of the physiological and therapeutic roles of this receptor. During the previous funding period, we found that hyperglycemia, associated with either insulin resistance or insulin insufficiency, caused an increase in AT2 receptor expression in the renal proximal tubule. Selective activation of the AT2 receptors stimulated a nitric oxide/cGMP pathway, thus inhibiting proximal tubule Na,K-ATPase (NKA) activity and increasing urinary Na excretion in obese Zucker rats, a model of insulin resistance and hyperglycemia. Treatment of obese rats with an AT2 receptor antagonist for 2 weeks raised BP in these animals. Three hypotheses were developed from these observations. First, hyperglycemia increases AT2 receptor expression by transcriptional activation. Second, selective AT2 receptor activation directly inhibits NKA via a NO/cGMP pathway and also, antagonizes the AT1 receptor-mediated NKA stimulation in proximal tubules by cGMP- mediated inhibition of phosphodiesterase-3 (PDE-3). Third, long-term selective AT2 receptor activation increases urinary Na excretion and lowers BP in obese Zucker/diabetic rats. These hypotheses will be tested by 3 specific aims utilizing cell culture and whole animal models.
Aim 1 will study the role of p38 MAP kinase and transcription factors IRF-1 and C/EBP2 in increasing AT2 receptor expression by high glucose concentrations in HK-2 cells;renal AT2 receptor expression/function in obese rats with euglycemia.
Aim 2 will study the role of cGMP-mediated PDE-3 inhibition, as a novel mechanism responsible for AT2 receptor antagonism of AT1 receptor-stimulated NKA, in isolated proximal tubules of obese Zucker rats.
In aim 3, we will study the effect of long-term treatment with an AT2 agonist on renal function and BP in control in kidney- specific AT2 knock-down obese/lean Zucker rats. Following treatments, proximal tubule NKA activity and various components of the renin angiotensin system will be determined. Biochemical, immunological, molecular biology, fluorescence imaging and whole animal physiological methodologies will be employed to accomplish the proposed studies. These studies will elucidate the mechanisms regulating AT2 receptor in diabetes. Moreover, they will advance our understanding of the physiological role of the AT2 receptor in the long-term regulation of renal function and blood pressure control. Finally, the studies may clarify the potential of the AT2 receptor as an important therapeutic target providing a strong basis to develop selective non-peptide AT2 agonists.

Public Health Relevance

Obesity/diabetes is a major health problem in the United States. In diabetes, abnormal kidney function in handling sodium excretion leads to the development of hypertension. We propose to investigate the role of a novel target, namely the Angiotensin II AT2 receptor, to improve kidney function and lower blood pressure in an obesity/diabetic animal model.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Rys-Sikora, Krystyna E
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Auburn University at Auburn
Schools of Pharmacy
Auburn University
United States
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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
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
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; 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
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
Dhande, Isha; Ali, Quaisar; Hussain, Tahir (2013) Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: role in renoprotection in obese rats. Hypertension 61:1218-26
Ali, Quaisar; Wu, Yonnie; Hussain, Tahir (2013) Chronic AT2 receptor activation increases renal ACE2 activity, attenuates AT1 receptor function and blood pressure in obese Zucker rats. Kidney Int 84:931-9
Samuel, Preethi; Ali, Quaisar; Sabuhi, Rifat et al. (2012) High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT(2)R-MasR axis in obese Zucker rats. Am J Physiol Renal Physiol 303:F412-9

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