Blockade of Notch1 Signaling Alleviated Podocyte Injury in Lupus Nephritis Via Inhibition of NLRP3 Inflammasome Activation

To explore the role of Notch1 pathway in the pathogenesis of podocyte injury, and to provide novel strategy for podocyte repair in lupus nephritis (LN). Bioinformatics analysis and immunofluorescence assay were applied to determine the expression and localization of Notch1 intracellular domain1 (NICD1) in kidneys of LN patients and MRL/lpr mice. The stable podocyte injury model in vitro was established by puromycin aminonucleoside (PAN) treatment. Expression of inflammasome activation related gene was detected by qPCR. The podocytes with PAN treatment were cultured with or without N-S-phenyl-glycine-t-butylester (DAPT), an inhibitor of Notch1 pathway. NICD1, Wilm’stumor1 (WT1), nucleotide-binding oligomerization domain-like receptors 3 (NLRP3), and absent in melanoma-like receptors 2 (AIM2) were detected by western blot. In vivo , MRL/lpr mice were administrated with DAPT or vehicle. The LN symptoms were assessed. The podocyte injury was evaluated, and the NLRP3 in podocytes of mice was detected. Notch1 pathway was overactivated in glomeruli of LN patients. NICD1 was colocalized with podocytes of LN patients and MRL/lpr mice. The inflammasome-related genes were significantly increased in podocytes with PAN treatment. NICD1 and NLRP3 were significantly decreased, while WT1 was significantly increased in injured podocytes treated with DAPT in vitro . In vivo , lupus-like symptoms were alleviated in DAPT treatment group. Notch1 pathway was inhibited in kidneys of mice treated with DAPT. The renal inflammation was reduced and the podocyte injury was mitigated in DAPT treatment group. The NLRP3 was decreased in podocytes of mice treated with DAPT. Notch1 pathway was overactivated in podocytes of LN patients and MRL/lpr mice. Blockade of Notch1 pathway reduced renal inflammation and alleviated podocyte injury via inhibition of NLRP3 inflammasome activation in LN.

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