Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-ΚB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM), a syndrome characterized by skeletal muscle damage resulting in renal tubular oxidative stress, inflammation, and activated toll like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. Pyroptosis is a programmed cell death mediated by NLRP-3 leading to the activation of caspase-1 and gasdermin D (GSDMD), the hallmark of pyrop-tosis. This study aims to investigate the renoprotective effects of two antioxidants; pentoxifylline (PTX) and thiamine (TM) via targeting the aforementioned pathways. RM-AKI was induced in male Albino Wistar rats by intramuscular injection of glycerol (50% v/v, 10 ml/kg). PTX (100 mg/kg, oral) and TM (25 mg/kg, i.p) were administered for 12 days prior glycerol injection and continued for 3 days following induction of RM-AKI. Serum creatinine, blood urea nitrogen (BUN), creatin kinase, lipid peroxides, total antioxidant activity, inflammatory markers (tumor necrosis factor-alpha, interleukin-1 beta, and nuclear factor kappa B), TLR4, NLRP-3, caspase-1, GSDMD and c-myc (an apoptotic marker) were estimated. Compared to AKI model, co-administered drugs revealed a significant improvement in renal function and pathology as indicated by the reduction in serum creatinine, BUN and protein cast accumulation. The elevations of oxidative stress, and inflammatory markers as well as the over-expression of c-myc were alleviated. Protein levels of TLR4, NLRP3, cleaved caspase-1, and GSDMD were significantly elevated in RM-AKI model, and this elevation was attenuated by the tested drugs. In conclusion, PTX and TM could be a potential renoprotective approach for patients with RM through targeting TLR4/NF-kappa B and NLRP-3/caspase-1/gasdermin mediated-pyroptosis pathways.

Automated summary

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM) characterized by muscle damage leading to renal oxidative stress, inflammation, and activation of toll-like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. This study investigates the protective effects of antioxidants pentoxifylline (PTX) and thiamine (TM) on these pathways. The results show that PTX and TM improve renal function, reduce oxidative stress and inflammation, and attenuate the over-expression of apoptotic marker c-myc and proteins associated with pyroptosis.