Modulatory role of angiotensin II in the gene expression of renin/prorenin receptor (RPR)in the kidneys from diabetic animals

• Grant number: 10/16338-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2011
• End date: December 31, 2011
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Mirian Aparecida Boim
• Grantee: Rosemara Silva Ribeiro
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

INTRODUCTION: Renin and prorenin bind to (pro)renin receptor ((P)RR) resulting in increased synthesis of Ang II and activation of MAP kinases family ERK 1/2. The (P)RR was cloned in mesangial cells (MC) and experimental data strongly suggest that it has a central role in diabetic glomerulosclerosis by Ang II-dependent and independent pathways. We observed previously that silencing (P)RR gene prevented the mesangial matrix overproduction induced by high glucose concentration in MC. On the other hand, the blockade of AT1 receptor by losartan induced significant reduction in expression levels of (P)RR in these cells and also reversed the effects of glucose on mesangial matrix overproduction. These results suggest that, least in vitro, there may be an interaction between AT1 receptors and (P)RR function or the expression of (P)RR could be under the modulatory control of Ang II.Objective: To test this hypothesis it will be evaluated wheather the blockade of AT1 receptor or inhibition of Ang II synthesis would be able to change (P)RR expression in kidneys of diabetic rats.Methods: The diabetes will be induced in adults Wistar rats by administration of streptozotocin (60mg/kg, e.v.). After 30 days of diabetes induction, the animals will be divided in 5 groups: diabetic; diabetic treated with losartan (50mg/kg, vo), diabetic treated with ACE blocker, captopril (50mg/kg, vo); diabetic treated with renin blocker, aliskiren (50mg/kg, vo) and diabetic treated with vitamin D, an agent recently shown to suppress prorenin gene activity (3µg/kg, sc). The animals will be treated for 30 days. In the end of the treatments, animals will be sacrificed and kidneys removed to subsequent analysis. The expression of ERK 1/2, fibronectin, (P)RR, renin and prorenin by immunohistochemistry, western blot and RT-PCR. Plasma and intrarenal level of Ang II will be inferred through of ELISA.