Endoplasmic reticulum stress contributes to pyroptosis through NF-κB/NLRP3 pathway in diabetic nephropathy

Aims: Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. Endo plasmic reticulum (ER) stress and pyroptosis play a critical role in the pathological process of DN, but their mechanism in DN has been litter attention.Main methods: Here, we firstly used large mammal beagles as DN model for 120 d to explored the mechanism of endoplasmic reticulum stress-mediated pyroptosis in DN. Meanwhile, 4-Phenylbutytic acid (4-PBA) and BYA 117082 were added in the MDCK (Madin-Daby canine kidney) cells by high glucose (HG) treatment. ER stress and pyroptosis related factors expression levels were analyzed by immunohistochemistry, immunofluorescence, western blotting, and quantitative real-time PCR assay.Key findings: We identified that glomeruli atrophy, renal capsules were increased, and renal tubules thickened in diabetes. Masson and PAS staining resulted showed that the collagen fibers and glycogen were accumulated in kidney. Meanwhile, the ER stress and pyroptosis-related factors were significantly activated in vitro. Importantly, 4-PBA significantly inhibited the ER stress, which also alleviated the HG-induced pyroptosis in MDCK cells. Furthermore, BYA 11-7082 could reduce the expression levels of NLRP3 and GSDMD genes and proteins.Significance: These data provide evidence for ER stress contributes to pyroptosis through NF-?B/NLRP3 pathway in canine type 1 diabetic nephropathy.