New insights in amelioration of rhabdomyolysis-induced acute kidney injury by triple effect of Diallyl trisulphide and Sildenafil on apoptosis, NF-κB and NRF-2/HO-1 signaling crosstalk

Abstract Acute kidney injury is a crucial complication of rhabdomyolysis. Glycerol (Gly) is used for induction of rhabdomyolysis in rats. Diallyl trisulphide (DATS) is a natural product from garlic with reported anti-inflammatory/antioxidant activities. Sildenafil (Sild) is a phosphodiesterase-5 inhibitor, selected in this study for its experimental protective effects in muscle and kidney injuries. Herein, protective effects of DATS and Sild were investigated in rhabdomyolysis-induced acute kidney injury (RIAKI) model. Rats were separated into five groups: Control (saline, i.p.), Gly (10 ml/kg, i.m.), Gly+Sild (5mg/kg, oral), Gly+DATS (10 and 20 mg/kg, i.p.), and tested 24 hrs after injury. Renal and muscle function tests: Serum BUN, creatinine, total CK, CK-MB, in addition to urine creatinine, total protein and albumin were measured. Renal oxidant/antioxidant status and histopathological changes, were also measured. Meanwhile, renal NRF-2, HO-1, IL-1β and IL-6, were assessed by ELISA. Furthermore, inflammation (TNF-α, NF-κBp65, COX-2) and apoptosis (BAX/BCL-2) were examined by immunohistochemistry. The study showed that DATS, in a dose-dependent manner improved RIAKI, through reduction of mortality, renal damage, muscle injury, oxidative stress inflammation and apoptosis, in addition to improvement of kidney function and anti-oxidant defense. DATS prevented nuclear translocation of NF-κBp65 and BAX. Otherwise, DATS elevated nuclear translocation of BCL-2 and expression of NRF-2/HO-1, thus modulating the crosstalk between these pathways. In the meantime, sildenafil, to a reduced extent, monitored the same pathways and proved its muscle/reno-protective actions. Therefore, DATS can be a natural candidate for treatment of acute muscle and kidney injuries, via its verified antioxidant, anti-inflammatory and antiapoptotic potentials.