Effect of Prorrenin/Renin Receptor Inhibition upon Immune Cells Signaling and Blood Pressure in An Experimental Model of Hypertension

Abstract

Introduction Hypertension is a multifactorial disease. Several systems participate in its pathophysiology. The renin-angiotensin-aldosterone system (RAAS) and the immune system (IS) participate actively in maintaining inflammation and other alterations in the cardiovascular system. Interestingly, both systems, cardiovascular and the IS, share the expression and activity of prorenin/renin receptor (P)RR in different cells, as endothelial cells, cardiomyocytes, lymphocytes and NK cells, suggesting an orchestrated action during hypertension. Aim To evaluate the effect of prorrenin/renin receptor inhibition upon immune cells and blood pressure in 5/6 nephrectomized rats. Methods We used male Wistar rats of 250 ± 20 g submitted to a 5/6 nephrectomy. Control rats were submitted to sham operation. The animals were randomly distributed in 7 days and 15 days groups (n = 4, each group). HRP peptide was administered subcutaneously at a dose of 0.2 mg/kg, every 24 hours, during the last 4 days of each time period. Control animals received vehicle. We measured blood pressure and animals were sacrificed, the spleen was processed for flow cytometry to determine PRR and intracellular pH, and for immunoblot to determine PRR, DVL-1, PLZF using beta-actin as housekeeping protein. Procedures in animals complied with the requirements of the NOM – 062 – ZOO – 1999, and the NIH Guide for the Care and Use of Laboratory Animals. Results 5/6 nephrectomy groups had an increase in blood pressure compared to controls. HRP treatment decreased blood pressure significantly in nephrectomized groups. Seven days nephrectomy group increased PRR expression in lymphocytes and NK cells. HRP treatment reverted this effect; in the 15 days nephrectomized group there were no significant differences. DVL-1 and PLZF were measured in both groups. We found that, in the nephrectomy groups, these proteins had a higher expression compared to controls, and PRR blockade decreased this expression significantly. The intracellular pH in polymorphonuclear cells and lymphocytes was more acidic in the nephrectomy groups compared to the control group. This effect was reverted by treatment. Conclusion The PRR increased its expression in immune cells during hypertension. Treatment with HRP decreased this expression and reverted high blood pressure in early times. This effect seems to involve V-ATPase activity by affecting intracellular pH and the activation of the canonical WNT pathway