Relaxin signaling in testis: investigation of the presence of isoforms of the RXFP1 receptor, NOS/NO signaling, and the possible participation of the glucocorticoid receptor

• Grant number: 14/05028-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2014
• End date: May 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Maria de Fátima Magalhães Lazari
• Grantee: Carla Macheroni Lima
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Relaxin is an insulin-related peptide with pleiotropic actions in the body. In 2002, the G protein-coupled receptor RXFP1 was identified as the relaxin receptor. However, although the relaxin knockout leads to infertility in males, the RXFP1 knockout does not perfectly mimic this phenotype. Furthermore, the most well known signaling pathway stimulated by RXFP1 is the increase of cAMP production, but relaxin does not stimulate this pathway in testis. Previous studies from our laboratory revealed that relaxin and RXFP1 are present in the testis, where the peptide exerts important effects on spermatogenesis. Relaxin stimulates proliferation of immature Sertoli cells through the activation of MEK-ERK1/2 and PI3K-AKT pathways. Moreover, relaxin inhibits cAMP production in rat Sertoli cells after 30 min incubation. One of the alternative splice variants of RXFP1 can act as antagonist of the action of the peptide. On the other hand, some actions of relaxin, including activation of the NO/cGMP/PKG pathway, appear to involve the participation of the glucocorticoid receptor (GR). Relaxin activates the production of NO by activating endothelial nitric oxide synthase (eNOS or NOS3) or by inducing gene expression of inducible NOS (iNOS or NOS2), and this effect may involve activation of ERK1/2 and PI3K-AKT pathways. In the testis, NO plays an important role both in the regulation of the dynamics of adherens junctions between Sertoli and germ cells, and in the control of hormone and cytokines levels. The aim of this study is to characterize, in cultured testicular cells: 1) the isoforms of RXFP1, 2) the role of relaxin on the activation of NOS2 and NOS3, and the interplay between this pathway and the activation of MEK-ERK1/2 and PI3K/AKT pathways, 3) the role of GR in the relaxin signaling.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NASCIMENTO, ALINE R.; MACHERONI, CARLA; LUCAS, THAIS F. G.; PORTO, CATARINA S.; LAZARI, MARIA F. M.. Crosstalk between FSH and relaxin at the end of the proliferative stage of rat Sertoli cells. Reproduction, v. 152, n. 6, p. 613-628, DEC 2016. (10/10274-2, 14/05028-3, 14/08563-7, 11/14262-1)