Pharmacotherapeutic role of astringin against chromium induced nephrotoxicity via modulating TLR4/MyD88, HMGB1/RAGE and NF-κB pathway: A biochemical and pharmacokinetic approach

Abstract

Background: Chromium (Cr) is a noxious heavy metal that is reported to induce various organ damages including the kidneys. Astringin (ATN) is a polyphenolic flavonoid that demonstrates immense pharmacological potential.

Aim: This research was planned to assess the potential palliative efficacy of ATN against Cr induced renal toxicity via regulating biochemical and histological parameters.

Methodology: Thirty-two male albino (Sprague Dawley) rats were divided into four groups: the 1st group (control), 2nd group (Cr 15 mg/kg), 3rd group (Cr 15 mg/kg + ATN 10 mg/kg), and 4th (ATN 10 mg/kg) group. Gene profile was evaluated by using qRT-PCR protocol. The levels of other biochemical parameters were assessed through standard ELISA protocol as well as already reported standard assays. Histology was performed as per the basic principle of histopathology technique. The palliative role of ATN was further confirmed by molecular docking (MD) and molecular dynamic simulation (MDS) approach.

Results: Cr intoxication upregulated the gene expression of high mobility group box1 (HMGB1), tumor necrosis factor- α (TNF-α), nuclear factor- kappa B (NF-κB), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), myeloid differentiation primary response 88 (MYD88), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and interleukin-1β (IL-1β). The levels of reactive oxygen species (ROS) and malondialdehyde were elevated while the activities of glutathione reductase (GSR), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1), superoxide dismutase (SOD) & catalase (CAT) as well as contents of glutathione (GSH) were reduced after Cr intoxication. Moreover, Cr exposure increased the levels of cystatin C, uric acid, neutrophil gelatinase-associated lipocalin (NGAL), creatinine, blood urea nitrogen (BUN), N-acetylglucosamine (NAG), kidney injury molecule-1 (KIM-1) & urea while downregulating the concentrations of creatine clearance. Besides, the levels of B cell lymphoma-2 (Bcl-2) were reduced while the levels of cysteine-aspartic acid protease-9 (Caspase-9), Bcl-2-associated X protein (Bax) and cysteine-aspartic acid protease-3 (Caspase-3) were escalated after Cr intoxication. Renal tissues showed abnormal histology following the exposure to Cr. Nonetheless, ATN treatment effectively restored biochemical as well as histological impairments in renal tissues, thereby demonstrating the nephroprotective potential against Cr intoxication.

Conclusion: ATN therapy showed significant renal protection via suppressing oxidative stress, inflammation, apoptosis and histological damages. These findings emphasize the important role of ATN in regulating renal health via modulating TLR4/MyD88, HMGB1/RAGE and NF-κB signaling pathway.

Keywords: Astringin; Chromium; Inflammation; Redox balance; Renal toxicity.