Berberine Ameliorates Diabetic Kidney Disease by Modulating Macrophage Polarization via Inhibiting IL-17A Signaling.

Objective: This study aimed to elucidate the molecular mechanisms of berberine (BBR) in ameliorating diabetic kidney disease (DKD), focusing on its regulatory effects on the renal immune microenvironment and macrophage polarization. Methods: We first employed a network pharmacology approach, integrating public transcriptomic data with drug target databases, to predict the core pathways and immune regulatory mechanisms of BBR in DKD. To experimentally validate these in silico predictions, we assessed the effects of BBR on apoptosis, fibrosis, and inflammation in a high-glucose-induced renal tubular epithelial cell (NRK-52E) model. Finally, a DKD rat model was established to confirm the therapeutic efficacy in vivo and to mechanistically investigate BBR's impact on renal macrophage polarization and the key signaling proteins of the predicted pathway. Results: Network pharmacology and transcriptomic analysis identified 55 core genes of BBR in DKD, enriched in apoptosis, metabolism, oxidative stress, and inflammation, with immune infiltration implicating T cells, B cells, and macrophage subsets. In vitro, BBR enhanced viability of high-glucose-injured NRK-52E cells, suppressed apoptosis and fibrosis markers, and reduced IL-6, IL-17A, and TNF-α levels. In vivo, BBR reduced hyperglycemia, preserved renal function, attenuated fibrosis, and rebalanced macrophage polarization by inhibiting M1 while promoting M2 phenotypes. Mechanistically, these effects were associated with downregulation of the IL17A/TRAF6/MAPK14 pathway. Conclusion: Berberine alleviates diabetic kidney disease by regulating macrophage polarization via inhibition of the IL17A/TRAF6/MAPK14 signaling pathway, underscoring its therapeutic potential as an anti-inflammatory and anti-fibrotic agent.