The conserved molecular mechanism of erectile dysfunction in type 2 diabetes rats and mice by cross-species transcriptomic comparisons.

Abstract

Background: The poor clinical situation of type 2 diabetes-induced erectile dysfunction (T2DMED) creates an urgent need for new therapeutic targets.

Aim: To reveal the conserved molecular mechanism of T2DMED across species.

Methods: T2DMED rat and mouse models were constructed to extract mRNA from corpus cavernosum for high-throughput sequencing. The differentially expressed genes (DEGs) were analyzed and the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction Networks were performed by bioinformatics methods. Immunohistochemistry, immunofluorescence, hematoxylin- eosin and Masson staining were used for subsequent verification.

Outcomes: Cross-species transcriptomics of T2DMED rats and mice were analyzed and validated.

Results: Gene expression patterns in normal corpus cavernosum of mice and rats showed a strong correlation (r = 0.75, P < 2.2 × 10^-16), with a total of 15 691 homologous genes identified. In both species, 553 homologous down-regulated DEGs were identified, mainly enriched in pathways related to smooth muscle and mitochondrial functions, as revealed by KEGG and GO analyses. Immunohistochemistry and immunofluorescence confirmed the decreased expression of α-smooth muscle actin and Uqcr10 in cavernosum tissues of T2DMED mice and rats. Additionally, 239 homologous up-regulated DEGs were identified, which were enriched in the Wnt signaling pathway and extracellular matrix composition. Subsequent experiments confirmed increased β-catenin expression and significant collagen accumulation, indicating fibrosis in T2DMED.

Clinical implications: To provide a new direction for improving the erectile ability of patients with T2DMED.

Strengths and limitations: The main strength is that cross-species transcriptomic sequencing has revealed the conserved molecular mechanisms of T2DMED. The main limitation is the lack of further validation in the T2DMED patients.

Conclusions: Cross-species transcriptomic comparisons may offer a novel strategy for uncovering the underlying mechanisms and identifying therapeutic targets for T2DMED.