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Targeting TLR4 with ligustrazine and AT1R with telmisartan ameliorates diabetic kidney disease
Pratik Shankar Rakshe1, Anil Bhanudas Gaikwad1
1Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Vidya Vihar, Pilani, Rajasthan, 333031, India.
Abstract:
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.
Insights
A novel ligustrazine-telmisartan combination therapy shows significant renoprotective effects in diabetic kidney disease (DKD) models. This combination reduces inflammation and fibrosis, offering improved outcomes and potentially lower side effects compared to monotherapy.
Area of Science:
- Nephrology
- Pharmacology
- Diabetology
Background:
- Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD).
- Existing treatments for DKD leave significant residual risk, necessitating novel therapeutic strategies.
- Toll-like receptor 4 (TLR4) and angiotensin II type 1 receptor (AT1R) signaling pathways are implicated in DKD pathogenesis.
Purpose of the Study:
- To investigate the therapeutic potential of a novel combination of ligustrazine and telmisartan in preclinical models of DKD.
- To evaluate the effects of the combination therapy on key molecular pathways involved in DKD, including TLR4 and AT1R signaling.
- To assess the anti-inflammatory and anti-fibrotic properties of the ligustrazine-telmisartan combination.
Main Methods:
- DKD was induced in Sprague-Dawley rats using streptozotocin, followed by treatment with ligustrazine, telmisartan, or their combination.
- In vitro studies utilized high-glucose-stimulated NRK-52E cells treated with ligustrazine, telmisartan, and their combination.
- Analyses included biochemical assays, histological examination, immunohistochemistry, immunocytochemistry, and immunoblotting to assess renal function, inflammation, and fibrosis markers.
Main Results:
- The ligustrazine-telmisartan combination significantly improved metabolic and renal function in diabetic rats, preserving renal architecture.
- Co-treatment suppressed key inflammatory and fibrotic pathways, including TLR4/NF-κB/NLRP3 and AT1R/TGF-β/β-catenin, and reduced pro-inflammatory cytokines (IL-18, IL-1β) and caspase-1.
- In vitro, the combination therapy reduced markers of inflammation and fibrosis (TLR4, p-NF-κB, α-SMA, vimentin, collagen-I) in kidney cells.
Conclusions:
- The combination of ligustrazine and telmisartan demonstrates superior anti-inflammatory and anti-fibrotic effects in DKD models compared to monotherapies.
- This combination therapy enhances renoprotection and allows for a reduced dose of telmisartan, potentially mitigating side effects.
- Ligustrazine-telmisartan combination therapy represents a promising strategy for improving therapeutic outcomes in patients with diabetic kidney disease.
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