Abatacept-Loaded Podocyte-Derived Exosomes Alleviate Membranous Nephropathy via AhR-Regulated NF-κB/Nrf2 Signaling under Oxidative Stress and Inflammation.

Membranous nephropathy (MN) is a major cause of adult nephrotic syndrome characterized by immune complex deposition and podocyte injury. Oxidative stress and chronic inflammation contribute significantly to disease progression. The present study was conducted to explore the therapeutic effects of podocyte-abatacept loaded exosomes (Abt@Exos) on MN through regulating aryl hydrocarbon receptor (AhR) regulated nuclear factor-kappa B (NF-κB)/ nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Abt@Exos were identified using scanning electron microscopy (SEM) and nanoparticle tracking analysis (NTA). An animal model of MN was induced in Passive Heymann nephritis (PHN) rats, where the exosome therapy was administered intravenously every three days for three weeks. The parameters like renal function, inflammation, oxidative stress biomarkers, and pathology were estimated. RT-qPCR analysis was used to determine the gene expressions of β-actin, CYP1A1, CYP1A2, CYP1B1, AhR, NF-κB p65, Nrf2, IL-6, TNF-α, and COX-2. Abt@Exos administration showed effective results on proteinuria and renal pathological changes, upregulation of Nrf2 and HO-1 gene expressions, inhibition of NF-κB signaling pathway. In addition, treatment decreased reactive oxygen species (ROS), malondialdehyde (MDA), and pro-inflammatory cytokine levels while restoring superoxide dismutase (SOD) activity. These findings indicate that Abt@Exos improved renal injury in membranous nephropathy by restoring redox balance and suppressing inflammation through modulation of AhR-regulated Nrf2/NF-κB signaling pathways.