Total Glucosides of Paeony Alleviates Acute Kidney Injury by Inhibiting Dendritic Cells and T-Cell Communication.

Aim: This study was designed to evaluate the renoprotective action of total glucosides of paeony (TGP) against cisplatin (Cis)-induced AKI and to delineate the molecular mechanisms.

Methods: AKI was induced in mice via a single intraperitoneal injection of Cis (20 mg/kg). Renal morphological changes were examined using hematoxylin and eosin (H&E) staining, while kidney function and oxidative stress markers were quantitatively assessed. Flow cytometry (FCM) was employed to profile immune cell differentiation and functional status. The mRNA and protein levels of kidney injury-related biomarkers were measured by quantitative real-time PCR (qPCR) and Western blotting, respectively. To unravel the mechanistic basis, key signaling cascades were probed in both renal tissues and isolated immune cells.

Results: Administration of TGP attenuated renal histological damage and diminished inflammatory cell infiltration in AKI mice. Notably, TGP recalibrated the function of bone marrow-derived dendritic cells (BMDCs), steering them away from a fully mature phenotype. This was evidenced by a marked reduction in the migratory marker C-C motif chemokine receptor 7 (CCR7) and a reciprocal elevation of the immunoinhibitory checkpoint programmed cell death ligand 1 (PD-L1). Importantly, this phenotypic shift was linked to TGP-induced metabolic reprogramming, as DCs from TGP-treated animals exhibited diminished mitochondrial membrane potential (MMP). The TGP-mediated DC reprogramming translated into a fundamentally rebalanced T-cell compartment: The cytotoxic CD8⁺ effector T cell was actively restrained, while the immunosuppressive regulatory T-cell (T_reg) subset was preferentially expanded. This modulation was further reinforced by elevated programmed cell death protein 1 (PD-1) surface expression on T cells. Mechanistic interrogation revealed that TGP concurrently dismantled two interconnected pro-inflammatory signaling nodes essential for DC-T cell communication. By attenuating TLR4/MyD88 recruitment, TGP curtailed the downstream nuclear translocation of NF-κB, thereby limiting the transcriptional output of DC-derived inflammatory cytokines that drive T-cell polarization. Concomitantly, TGP directly interfered with the JAK2/STAT3 module, not only diminishing its phosphorylation but also de-repressing the negative feedback regulator SOCS3. This dual blockade synergistically extinguished the inflammatory amplification loop instigated by Cis in the renal microenvironment.

Conclusion: Collectively, these findings indicate that TGP exerts a protective effect against Cis-induced AKI by rebalancing immune cell homeostasis and interfering with pro-inflammatory signaling networks, positioning it as a promising candidate for future AKI pharmacotherapy.