The epidemic of obesity, currently affecting more than 36.5% 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, into plasma. 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. New preliminary data showed that the infusion of a recombinant mouse sPRR in mice fed a standard diet activated local and circulating RAS by increasing renal cortical angiotensinogen (AGT) and circulating renin levels. Consistent with those results, our new results demonstrated that elevated plasma sPRR in adipose PRR KO mice is associated with an increase of cortical angiotensin II levels in the kidney. Urinary vasopressin levels also increased significantly in these mice. Together with our prior work, these results raise the possibility that sPRR regulates the renin angiotensin system (RAS) and body fluid volume. To test this idea, 3T3-L1 cells and human HepG2 cells were incubated with increased concentration of recombinant mouse sPRR. We found that sPRR increased the expression of AGT gene in 3T3-L1 cells and the secretion of AGT in the media of human HepG2. In addition, the incubation with our sPRR neutralizing antibody decreased AngII levels in the media of 3T3-L1 cells. Because sPRR infusion in mice 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 the renin gene. Thus, we propose that obesity stimulates sPRR production leading to hypertension through a mechanism that involves the activation of the RAS and increases AVP. We will test the hypothesis that tissue-derived sPRR mediates angiotensin II-induced hypertension associated with obesity, likely by amplifying the local AGT and renin response and increases urinary AVP. 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.
Obesity is the leading risk factor for cardiovascular diseases and increases all cause of death in USA and the risk of hypertension. We found a new molecule in the fat, liver and kidney that can help to cure hypertension associated with obesity.
