The Sigma-1 Receptor Exacerbates Cardiac Dysfunction Induced by Obstructive Nephropathy: A Role for Sexual Dimorphism
Francisco Javier Munguia-Galaviz,
Alejandra Guillermina Miranda-Diaz,
Yanet Karina Gutierrez-Mercado,
Marco Ku-Centurion,
Ricardo Arturo Gonzalez-Gonzalez,
Eliseo Portilla-de Buen,
Raquel Echavarria
Affiliations
Francisco Javier Munguia-Galaviz
Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
Alejandra Guillermina Miranda-Diaz
Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
Yanet Karina Gutierrez-Mercado
Departamento de Clinicas, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlan 47620, Jalisco, Mexico
Marco Ku-Centurion
Unidad de Biotecnologia Medica y Farmaceutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Jalisco, Mexico
Ricardo Arturo Gonzalez-Gonzalez
Division de Investigacion Quirurgica, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico
Eliseo Portilla-de Buen
Division de Investigacion Quirurgica, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico
Raquel Echavarria
Consejo Nacional de Humanidades, Ciencias y Tecnologias (CONAHCYT)—Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico
The Sigma-1 Receptor (Sigmar1) is a stress-activated chaperone and a promising target for pharmacological modulation due to its ability to induce multiple cellular responses. Yet, it is unknown how Sigmar1 is involved in cardiorenal syndrome type 4 (CRS4) in which renal damage results in cardiac dysfunction. This study explored the role of Sigmar1 and its ligands in a CRS4 model induced by unilateral ureteral obstruction (UUO) in male and female C57BL/6 mice. We evaluated renal and cardiac dysfunction markers, Sigmar1 expression, and cardiac remodeling through time (7, 12, and 21 days) and after chronically administering the Sigmar1 agonists PRE-084 (1 mg/kg/day) and SA4503 (1 mg/kg/day), and the antagonist haloperidol (2 mg/kg/day), for 21 days after UUO using colorimetric analysis, RT-qPCR, histology, immunohistochemistry, enzyme-linked immunosorbent assay, RNA-seq, and bioinformatics. We found that obstructive nephropathy induces Sigmar1 expression in the kidneys and heart, and that Sigmar1 stimulation with its agonists PRE-084 and SA4503 aggravates cardiac dysfunction and remodeling in both sexes. Still, their effects are significantly more potent in males. Our findings reveal essential differences associated with sex in the development of CRS4 and should be considered when contemplating Sigmar1 as a pharmacological target.
