Abstract Body: Diabetic Kidney Disease (DKD) affects nearly 40% of individuals with diabetes and remains a leading cause of end-stage renal disease globally. A key driver of DKD progression is endothelial dysfunction, triggered by chronic hyperglycemia-induced oxidative stress and inflammation. Recent research highlights the regulatory role of long non-coding RNAs (lncRNAs) in endothelial biology and vascular homeostasis. Among them, the lncRNA CASC15 is highly conserved across mammals and predominantly expressed in endothelial and vascular-rich tissues, including the kidney. Inhibition of CASC15 has been linked to vascular senescence, suggesting a role in vascular aging and disease progression. However, CASC15 exhibits over 300 splicing isoforms in humans, but the specific contributions of these isoforms to vascular dysfunction remain unclear.
While Previous studies have shown upregulation of CASC15 in renal epithelial cells under high glucose, its regulation in the vascular endothelial cells under hyperglycemic stress is largely unexplored. We hypothesize CASC15 expression is isoform- and cell type–specific, and that certain isoforms may contribute to endothelial dysfunction and DKD through distinct mechanisms from those in epithelial cells.
To investigate this, we treated human umbilical vascular endothelial cells (HUVECs) to high (25 mM), and normal (4 mM) glucose for 24 and 48 hours, and assesed CASC15 isoform expression by RT-qPCR . We identified significant downregulation of isoform CASC15-202 at 24 hours under high-glucose conditions. Loss of this isoform was associated with increased β-galactosidase activity, indicative of endothelial senescence.
These findings suggest a regulatory role for CASC15, particularly isoform 202, in endothelial responses to hyperglycemia. Future studies will examine the effects of prolonged high-glucose exposure in HUVECs and microvascular endothelial cells, and investigate CASC15 isoform regulation in vivo using Akita diabetic mice with unilateral nephrectomy. This work lays the foundation for elucidating CASC15-mediated mechanisms in diabetic vascular disease.