MiR-509-3p Targets YAP1 to Regulate Inflammatory Cytokines Against Hyperglycemia-Induced Renal Tubular Cell Damage in...

Hyperglycemia-induced renal inflammation and the subsequent activation of inflammatory cytokines play critical roles in Diabetic Kidney Disease (DKD) progression. However, the underlying molecular mechanisms, particularly those involving microRNAs, remain poorly understood.

Serum samples from DKD patients (n = 10) and healthy controls (n = 10) were subjected to microRNA transcriptome profiling. An in vitro DKD model was established by treating Human Renal Tubular Epithelial Cells (RTECs and HK-2) with High Glucose (HG). The levels of pro-inflammatory cytokines, Interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor (TNF)-α, were assessed using quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. Dual-luciferase reporter assays evaluated the relationship between miR-509-3p and Yesassociated protein 1 (YAP1). In situ hybridization and immunohistochemistry were performed to validate the expressions of miR-509-3p and YAP1 in kidney tissues from DKD patients (n = 38) and controls (n = 38).

MiR-509-3p was identified as one of the most significantly dysregulated microRNAs in the serum of DKD patients. Its expression was significantly downregulated in a dose-dependent manner in HG-induced RTECs and HK-2 cells (p <0.01). Overexpression of miR-509-3p significantly suppressed HG-induced pro-inflammatory cytokine expression (p <0.01). Suppression of miR-509-3p further enhanced HG-induced IL-1β, TNF-α, and IL-6 expression, whereas this effect was reversed by silencing YAP1 (p <0.01). Mechanistically, miR-509-3p directly targeted the 3'-UTR of YAP1 mRNA. Consistently, DKD renal tissues exhibited reduced miR-509-3p and elevated YAP1 expression, with a significant negative correlation (p = 0.002). Furthermore, miR-509-3p and YAP1 were significantly correlated with estimated glomerular filtration rate and urine albumin-creatinine ratio (p <0.001).

The study preliminarily suggests that miR-509-3p/YAP1 axis may act as a crucial regulator of hyperglycemia-induced tubular inflammation, offering a potential therapeutic target for DKD.