Targeting TLR4 with ligustrazine and AT1R with telmisartan ameliorates diabetic kidney disease.

Diabetic kidney disease (DKD) is a major driver of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Despite existing therapeutic approaches, significant residual risk persists, highlighting the need for improved treatment strategies. TLR4 and AT1R signaling pathways play critical roles in DKD pathogenesis. The present study investigates the therapeutic potential of a novel ligustrazine-telmisartan combination in both in-vivo and in-vitro models of DKD. The streptozotocin (55 mg/kg, i.p.) was administered in Sprague-Dawley rats to induce Type-1 diabetes. After four weeks, animals were treated with ligustrazine (40 and 80 mg/kg/day, i.p.), telmisartan (10 mg/kg/day, p.o.), and combination (ligustrazine 40 mg/kg/day, i.p. + telmisartan 5 mg/kg/day, p.o.). Post-treatment, plasma, urine, and kidney tissues were collected and analyzed for biochemical, histological, and immunohistochemical parameters. In-vitro, high-glucose-rh-TGF-β1-stimulated NRK-52E cells were treated with ligustrazine-50 µM, telmisartan-10µM, and their combination, alongside TAK-242-100nM (TLR4 inhibitor control), and cell samples were processed for cell viability, morphology, immunocytochemistry and immunoblotting. The ligustrazine-telmisartan combination therapy significantly improved metabolic and renal function, while histology revealed notable preservation of renal architecture. The co-treatment significantly suppressed TLR4/NF-κB/NLRP3, AT1R/TGF-β/β-catenin, along with IL-18, IL-1β, and caspase-1 in diabetic rats, as revealed by immunohistochemistry and qRT-PCR. Moreover, co-treatment reduced TLR4, p-NF-κB, α-SMA, vimentin, and collagen-I expression in NRK-52E cells as assessed by immunocytochemistry and immunoblotting. Collectively, the combination therapy showed greater anti-inflammatory and antifibrotic potential than monotherapies. These findings indicate that ligustrazine with telmisartan enhances renoprotection and allows a lower telmisartan dose, potentially reducing its side effects and improving overall therapeutic outcomes in DKD.