Bruceine A derivative P1 alleviates renal inflammation via Tnfrsf12a pathway in diabetic nephropathy.

Background: Diabetic nephropathy (DN), the predominant driver of end-stage renal disease globally, remains therapeutic option in clinical practice. Bruceine A (BA) demonstrates nephroprotective properties, however, its clinical translation has been hindered by dose-limiting toxicities. We synthesized BA derivatives P1 to overcome the limitation, presenting a novel therapeutic candidate for DN management. This study aims to evaluate the therapeutic efficacy and investigate the molecular mechanisms of P1 against DN.

Methods: The safety profile of P1 was assessed through Cell Counting Kit-8 and acute toxicity experiments. The therapeutic efficacy of P1 was evaluated in vivo using a db/db mouse model of DN and in vitro using high glucose-induced MCs rat mesangial cells (MCs). Comprehensive analyses, including transcriptome sequencing, siRNA-mediated gene knockdown, molecular docking and molecular dynamics simulation were conducted to explore the mechanistic pathways influenced by P1.

Results: P1 exhibited minimal toxicity compared to BA and markedly reduced the expression of inflammatory and fibrotic markers, including IL-6, NF-κB, CCL2, FN1, and Col4a1 in vitro. In vivo, P1 effectively decreased the UACR and improved renal function, meanwhile, it could ameliorate the proliferation of MCs and reduce mesangial matrix deposition. Additionally, P1 lowered blood glucose levels and attenuated renal inflammatory responses. Mechanistic studies revealed that P1 down-regulated the gene and protein expression of Tnfrsf12a, thereby mitigating inflammatory injury in DN. Molecular docking and molecular dynamics simulation results demonstrate stable binding between P1 and AP1.

Conclusion: This study provides the first evidence that P1 modulates the Tnfrsf12a signaling pathway, thereby ameliorating renal inflammation and exerting a protective effect in DN. P1 presents a potential therapeutic candidate for treating DN.