Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

Francisco Javier Munguia-Galaviz; Yanet Karina Gutierrez-Mercado; Alejandra Guillermina Miranda-Diaz; Eliseo Portilla de Buen; Mario Eduardo Flores-Soto; Raquel Echavarria

doi:10.1016/j.heliyon.2024.e27468

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

Heliyon. 2024 Mar 8;10(6):e27468. doi: 10.1016/j.heliyon.2024.e27468. eCollection 2024 Mar 30.

Authors

Francisco Javier Munguia-Galaviz^{1

2}, Yanet Karina Gutierrez-Mercado³, Alejandra Guillermina Miranda-Diaz¹, Eliseo Portilla de Buen⁴, Mario Eduardo Flores-Soto⁵, Raquel Echavarria⁶

Affiliations

¹ Departamento de Fisiologia, CUCS, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico.
² Division de Ciencias de la Salud, CUSUR, Universidad de Guadalajara, Ciudad Guzman 49000, Jalisco, Mexico.
³ Departamento de Clinicas, CUALTOS, Universidad de Guadalajara, Tepatitlan 47620, Jalisco, Mexico.
⁴ Division de Investigacion Quirurgica, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico.
⁵ Division de Neurociencias, Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico.
⁶ CONAHCYT-Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico.

Abstract

Background: Cardiorenal syndrome (CRS) type 4 is prevalent among the chronic kidney disease (CKD) population, with many patients dying from cardiovascular complications. However, limited data regarding cardiac transcriptional changes induced early by CKD is available.

Methods: We used a murine unilateral ureteral obstruction (UUO) model to evaluate renal damage, cardiac remodeling, and transcriptional regulation at 21 days post-surgery through histological analysis, RT-qPCR, RNA-seq, and bioinformatics.

Results: UUO leads to significant kidney injury, low uremia, and pathological cardiac remodeling, evidenced by increased collagen deposition and smooth muscle alpha-actin 2 expression. RNA-seq analysis identified 76 differentially expressed genes (DEGs) in UUO hearts. Upregulated DEGs were significantly enriched in cell cycle and cell division pathways, immune responses, cardiac repair, inflammation, proliferation, oxidative stress, and apoptosis. Gene Set Enrichment Analysis further revealed mitochondrial oxidative bioenergetic pathways, autophagy, and peroxisomal pathways are downregulated in UUO hearts. Vimentin was also identified as an UUO-upregulated transcript.

Conclusions: Our results emphasize the relevance of extensive transcriptional changes, mitochondrial dysfunction, homeostasis deregulation, fatty-acid metabolism alterations, and vimentin upregulation in CRS type 4 development.

Keywords: CKD; Cardiorenal; Heart; Kidney; Transcriptomics; Uropathy; mRNA.