IL-12 Signaling Promotes Podocyte Senescence in Lupus Nephritis.

OBJECTIVE: Podocyte injury drives proteinuria and disease progression in lupus nephritis (LN), yet the mechanisms underlying podocyte dysfunction remain incompletely understood. METHODS: Sera from 39 SLE patients including 15 patients with LN and 13 healthy controls were collected. Levels of IL-12 were measured by enzyme-linked immunosorbent assay. Expression of IL-12 receptors (IL-12R) was assessed by immunofluorescence staining. Immortalized human podocyte cell line was used for in vitro study. The podocyte conditional knockout of Il12rb1 mice including B6.Il12rb1fl/flNphs2cre mice and B6.lpr.Il12rb1fl/flNphs2cre mice were generated. Accelerated lupus model and nephrotoxic nephritis model were induced. B6.Il12rb1fl/fl and B6.lpr.Il12rb1fl/fl mice were used as control. RESULTS: Serum levels of IL-12 were elevated in patients with LN (p=0.006) and in lupus-prone mice (p=0.041). Expression of the IL-12R was increased in podocytes in both human and murine LN. IL-12 stimulation induced the phosphorylation of calcium/calmodulin-dependent protein kinase 4 (CaMK4) and signal transducer and activator of transcription 4 (STAT4), causing mitochondrial dysfunction and increased reactive oxygen species accumulation leading to accelerated podocyte senescence, senescence-associated secretory phenotype and cytoskeleton disorganization. Podocyte-specific deletion of Il12rb1 attenuated podocyte senescence, ameliorated glomerular injury, and reduced proteinuria in both lupus-prone mice and normal mice injected with a nephrotoxic serum. CONCLUSION: Our findings identify IL-12 signaling as an important mediator of podocyte senescence in LN and suggest that targeting the IL-12-IL-12R axis may offer future therapeutic approaches to preserve podocytes and attenuate LN.