Adipocyte PRR Contributes to Obesity Induced Hypertension and Insulin Resistance

The epidemic of obesity has contributed to an increased prevalence of hypertension and type 2 diabetes in the US population. We recently demonstrated that adipose tissue becomes a predominant source of elevated circulating concentrations of angiotensin II (AngII) in obese hypertensive mice [1]. The adipose tissue expresses components of the renin-angiotensin system (RAS) that contribute to conversion of adipocyte-derived angiotensinogen (AGT) to AngII. Interestingly, adipocyte AGT deficiency prevented high fat-induced elevations in plasma angiotensin II concentrations and systolic blood pressure [1]. Amongst various components identified, we found that adipose tissue expresses the prorenin receptor (PRR), with a slight increased PRR mRNA abundance in adipose tissue from mice fed a high fat diet (HF). PRR binds renin or its inactive form, prorenin, leading to the cleavage of AGT to form angiotensin I (AngI). Recent studies report that the action of PRR to produce AngI from AGT may occur at the cell surface in adipocytes [2-4]. In this proposal, I will define whether PRR expression in adipose tissue of obese mice contributes to increased adipose-derived AngII and to the development of obesity-hypertension. In addition to generation of angiotensin peptides, the binding of renin/prorenin to the PRR also activates intracellular signaling pathways in mesangial cells, resulting in phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and the activation of transforming growth factor ß (TGFß) [5-8], a cytokine implicated in various cell process such as adipogenesis, fibrosis, inflammation and insulin resistance [9, 10]. These effects through PRR signaling are independent of production of AngII and will be named intracellular PRR signaling in this proposal [11]. Interestingly, recent studies report that intracellular PRR signaling is present in adipocytes [12]. However, increasing evidence also supports that AngII mediated effects via the angiotensin type 1 receptor (AT1R) in adipocytes that promote the development of inflammation and insulin resistance in adipose tissue [13]. Thus, both AngII-dependent pathways and intracellular PRR signaling may promote the development of obesity-associated insulin resistance. In this proposal, I will determine whether adipocyte PRR is involved in obesity-associated insulin resistance. To add another level of complexity, a soluble form of PRR (sPRR) is generated by intracellular cleavage of PRR by furin resulting in the production of a 28 kDa protein [14, 15]. sPRR is detected in plasma [14] and urine [16, 17] and could bind prorenin [16] and participate to AngI formation [17]. Our preliminary data demonstrate for the first time that sPRR is present in the media of 3T3-L1 cells and is increased during the differentiation of adipose tissue. Therefore, I will define whether sPRR is increased during the development of obesity and contributes to obesity related hypertension and insulin resistance. The working hypothesis of this proposal is that the adipocyte PRR contributes to the development of obesity-associated hypertension and insulin resistance. To test this hypothesis, we propose the following specific aims: Specific Aim 1. Determine whether adipocyte PRR is implicated in adipocyte-derived production of AngII during the development of obesity-hypertension. Specific Aim 2. Determine whether adipocyte PRR is involved in obesity related insulin resistance.