NR4A1 silencing alleviates high-glucose-stimulated HK-2 cells pyroptosis and fibrosis hindering NLRP3 activation and PI3K/AKT pathway.

BACKGROUND

The pathophysiology of diabetic kidney disease (DKD) is complex. Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression. Previous studies have revealed that nuclear receptor subfamily 4 group A member 1 (NR4A1) may serve as a novel pathogenic element in DKD; however, the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.

AIM

To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.

METHODS

Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD. Typically, 45 mmol/L glucose [high glucose (HG)] was used to activate HK-2 cells to mimic the DKD model . HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.

RESULTS

NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells. Concurrently, NOD-like receptor protein 3 (NLRP3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways were triggered, and pyroptosis and expression of fibrosis-linked elements was increased and . These alterations were significantly reversed NR4A1 silencing.

CONCLUSION

Inhibition of NR4A1 mitigated pyroptosis and fibrosis suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.