MicroRNA-122-5p Targets FOXO3 to Mediate Podocyte Senescence and Proteinuria Induced by Angiotensin II Type 1...

Preeclampsia (PE) drives irreversible podocyte depletion, predisposing patients to a heightened long-term risk of chronic kidney disease. While premature cellular senescence underlies this structural loss, the specific preeclamptic factors triggering this mechanism remain incompletely defined. We investigated the role of the angiotensin II type 1 receptor agonistic autoantibody (AT1-AA)-a central circulating pathogenic factor in PE-in promoting podocyte senescence through post-transcriptional pathways. We first interrogated public clinical transcriptomic datasets and validated the findings using clinical urine specimens from PE patients to identify key dysregulated microRNAs in PE. We then integrated in vitro mechanistic assays using human podocytes with an in vivo AT1-AA-infused pregnant mouse model. The regulatory cascade was validated via dual-luciferase reporter assays. The therapeutic efficacy of targeting this pathway was evaluated via systemic administration of a specific microRNA inhibitor (AntagomiR-122-5p). Bioinformatic analysis and clinical validation revealed that miR-122-5p is upregulated in PE patients. In vivo, AT1-AA exposure provoked classic PE manifestations, including severe hypertension, albuminuria, and podocyte foot process effacement. This pathology was driven by podocyte-specific senescence, evidenced by nuclear p21 accumulation and a senescence-associated secretory phenotype (SASP). Mechanistically, AT1-AA triggered a toxic accumulation of mitochondrial reactive oxygen species (mtROS) by upregulating miR-122-5p, which directly repressed the FOXO3/SOD2 antioxidant defense system. Targeted in vivo inhibition of miR-122-5p yielded dual therapeutic benefits: it attenuated the elevation in maternal systolic blood pressure and conferred direct cytoprotection to the glomerular filtration barrier. AntagomiR-122-5p effectively reversed glomerular senescence, suppressed local inflammatory cytokines, and restored podocyte ultrastructure. AT1-AA governs preeclamptic podocyte senescence and proteinuria by suppressing the FOXO3/SOD2 signaling axis via clinically relevant miR-122-5p. Systemic antagonism of miR-122-5p offers a comprehensive therapeutic strategy to simultaneously alleviate maternal hypertension and protect the renal filtration barrier from permanent structural decline.