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
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The Sigma-1 Receptor Exacerbates Cardiac Dysfunction Induced by Obstructive Nephropathy: A Role for Sexual Dimorphism.
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.
BiomedicinesBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.20
自引率
8.50%
发文量
2823
审稿时长
8 weeks
期刊介绍:
Biomedicines (ISSN 2227-9059; CODEN: BIOMID) is an international, scientific, open access journal on biomedicines published quarterly online by MDPI.