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

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  1   2 , Yanet Karina Gutierrez-Mercado  3 , Alejandra Guillermina Miranda-Diaz  1 , Eliseo Portilla de Buen  4 , Mario Eduardo Flores-Soto  5 , Raquel Echavarria  6
Affiliations

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 et al. Heliyon. .

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.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Kidney injury post-UUO. (A) Sham and UUO kidneys representative images. (B) Left kidney weight/Bw ratio. (C) Histological analysis of sham and UUO kidneys with PAS and Sirius red (400X, scale bar = 100 μm). Levels of (D) sCR (mg/dL) and (E) BUN (mg/dL). (F) Ngal/Gapdh fold-change by RT-qPCR. N = 5, **P < 0.005.
Fig. 2
Fig. 2
Pathological remodeling in UUO hearts. (A) Heart weight/Bw ratio. (B) Bnp/Gapdh fold-change by RT-qPCR. (C) Anp/Gapdh fold-change by RT-qPCR. (D) Histological analysis of sham and UUO hearts with H&E and Sirius red, and (E) ACTA2 immunohistochemical detection and quantification (400X, scale bar = 100 μm). N = 5, *P < 0.05.
Fig. 3
Fig. 3
DEGs in UUO hearts. (A) Box plot of log2(FPKM) values. (B) Volcano map showing the distribution of DEGs in UUO vs. sham hearts. (C) Heatmap plot of DEGs. Red = upregulated and blue = downregulated. P < 0.05 and log2 (fold change) > 1. N = 3.
Fig. 4
Fig. 4
Enrichment analysis in UUO hearts. (A) Enriched GO terms. Scatter plot of the top enriched 20 (B) GO terms (C) KEGG pathways. Circle sizes, number of enriched genes per pathway, and color, P-value range. N = 3.
Fig. 5
Fig. 5
GSEA analysis in UUO hearts. Top 20 negatively enriched pathways (A) GO, (B) KEGG, and (C) REACTOME. |NES|≥ 1, NOM p-val<0.05, and FDR q-val<0.25. N = 3.
Fig. 6
Fig. 6
RT-qPCR validation. (A) Log2 (fold change) expression changes between RNA-seq (N = 3) and RT-qPCR (N = 5) for CD300E, Esco2, Spag5, Hmmr, Foxm1, Plk1, Ctf1, Scand1, and Nrnt. (B) Linear regression plot. The log2 (fold-change) values for RNA-seq and qRT-PCR are plotted along with the linear fit line. A significant Spearmanʼs correlation coefficient is also shown.
Fig. 7
Fig. 7
Vimentin upregulation in UUO hearts. (A) Vim/Gapdh fold-change by RT-qPCR, *P < 0.05. (B) Vimentin immunohistochemical detection (400X, scale bar = 100 μm) and (C) quantification. N = 5.
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