Nephropathy is aggravated by fatty acids in diabetic kidney disease through tubular epithelial cell necroptosis and is alleviated by an RIPK-1 inhibitor

Introduction: Diabetic kidney disease (DKD), one of the leading causes end-stage renal disease, has complex pathogenic mechanisms and few effective clinical therapies. DKD progression is accompanied by loss resident cells, followed chronic inflammation extracellular matrix deposition. Necroptosis a newly discovered form regulated cell death major intrinsic in certain diabetic complications such as cardiomyopathy, intestinal retinal neuropathy; however, its significance largely unknown. Methods: In this study, expression necroptosis marker phosphorylated MLKL (p-MLKL) biopsy tissues patients with was detected using immunofluorescence semiquantified immunohistochemistry. The effects different disease-causing factors on activation human HK-2 cells were evaluated western blotting. db/db mice fed high-fat diet to establish an animal model significant tubule damage. Mice treated RIPK1 inhibitor RIPA-56 evaluate protective effects. mRNA transcriptome sequencing used explore changes signaling pathways after treatment. Oil red O staining electron macroscopy observe lipid droplet accumulation mouse tissues. Results: Immunostaining RIPK1/RIPK3/MLKL verified occurrence tubular epithelial (RTECs) DKD. level p-MLKL correlated positively severity functional, pathological damages, High glucose fatty acids main causing cells. Renal function deterioration injury accelerated, pathway activated diet. Application effectively reduced degree injury, inhibited activation, necroinflammation Conclusion: present study revealed role might provide new therapeutic target for treatment