The abnormal thyroxine signals triggers podocyte apoptosis in DN mice.

Abstract

Podocyte injury is a pivotal factor in the advancement of diabetic nephropathy (DN). The present study aimed to delineate the influence of disrupted thyroxine signaling on podocyte apoptosis in DN mouse models. We employed bioinformatics analyses, coupled with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assessments, to identify differentially expressed genes (DEGs) associated with thyroxine signaling in both human and murine DN datasets. Subsequently, we elucidated the function of thyroid hormone receptor α1 (THRA1) and nuclear receptor co-repressor 1 (NCOR1) on glomerular injury and podocytes apoptosis under hypothyroid and hyperglycemic conditions, respectively. Our findings highlight that hypothyroidism significantly alters glomerular gene expression profiles in DN mice leading to increased podocyte apoptosis. This effect occurs through a dual mechanism: on one hand, the upregulation of THRA1 expression induced by DN results in direct glomerular injury, which was further aggravated by hypothyroidism; on the other hand, the downregulation of NCOR1 expression thereby increases THRA1 activity levels. Our data suggests that disturbed thyroxin signals could trigger podocyte apoptosis and glomerular injury in DN mice, offering new insights into DN pathogenesis while laying groundwork for innovative therapeutic strategies.