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The epidemic of obesity, currently affecting more than 30% of the population in the United States, has contributed to a rise in the prevalence of hypertension. We recently found that obesity stimulated the secretion of the soluble form of the prorenin receptor (PRR), sPRR. While examining sPRR protein concentrations in tissues, we found an increase of sPRR protein levels in the liver, the adipose tissue and the kidney of control mice fed a high fat diet compared to mice fed a low fat diet. Using a mouse model of constitutive deletion of adipose PRR, our preliminary results demonstrated that elevated plasma sPRR is associated with an increase of cortical angiotensin II levels, urine vasopressin (AVP) levels and water reabsorption. Consistent with those results, in mice infused with sPRR, our preliminary data suggested that sPRR directly increased urine AVP levels. In addition, new data showed that the expression of angiotensinogen (AGT) gene is increased in the cortex of the kidney and that plasma renin level is increased in mice infused with sPRR. Together with our prior work, these results raise the possibility that sPRR regulates the renin angiotensin system (RAS) and fluid homeostasis. To test this idea, we have incubated 3T3-L1 cells and human HepG2 cells with increased concentration of recombinant mouse sPRR. We found that sPRR increased the expression of AGT gene and the secretion of AGT in the media. The incubation with our neutralizing sPRR antibody decreased AngII levels in the media of 3T3-L1 cells. Because sPRR increased plasma renin levels, we also investigated whether sPRR regulated the expression of renin in kidney. Interestingly, we found that sPRR binds to the promoter of renin. Thus, we propose that sPRR is a master regulator of the RAS and fluid homeostasis in hypertension associated with obesity. In this proposal, we will investigate the mechanism by which sPRR from different tissue sources (liver, kidney and adipose) is involved in the activation of local and systemic RAS and AVP to promote hypertension associated with obesity. We will also investigate whether blocking sPRR can be used as a treatment for hypertension associated with obesity. Outcomes will demonstrate whether obesity is regulated through a previously unrecognized pathway represented by upstream control of RAS and AVP by sPRR. Our studies point to a unique functional role for sPRR in hypertension associated with obesity.
|Effective start/end date||7/15/18 → 6/30/23|
- National Heart Lung and Blood Institute: $1,510,766.00