Venetoclax Elicits Nephrotoxicity Through TLR4/MyD88‐Mediated Innate Immune Activation and IFN‐γ Signaling

ABSTRACT Venetoclax (VTX) is a selective B‐cell lymphoma‐2 inhibitor which is used for adults with chronic lymphocytic leukemia. However, it induces severe organ toxicity including renal impairments. The current investigation was conducted to elucidate the nephrotoxic impacts of VTX in dose‐dependent manner. Thirty‐two male Sprague–Dawley rats were randomly divided into four groups including control (normal saline through oral gavage), VTX‐low dose (50 mg/kg/day through oral gavage), VTX‐moderate dose (75 mg/kg/day through oral gavage), and VTX‐high dose (100 mg/kg/day through oral gavage) for 28 days consecutively. Gene expressions were assessed through qRT‐PCR. The levels of inflammatory, apoptotic, and renal function markers were evaluated through ELISA. Administration of VTX caused significant upregulation of Interferon‐gamma (IFNG) , Interferon gamma receptor (IFNGR1) , Signal transducer and activator of transcription 1 (STAT1) , Interferon regulatory factor 1 (IRF1), Toll‐like receptor 4 (TLR4) , Myeloid differentiation primary response 88 (MYD88) , Interleukin‐1 receptor‐associated kinase 1 (IRAK1) and Tumor necrosis factor receptor‐associated factor 6 (TRAF6) . The activity of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), glutathione S‐transferase (GST), glutathione reductase (GSR) and hemeoxygenase‐1 (HO‐1) were significantly lowered while the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were augmented in response to VTX exposure in dose‐dependent manner. Moreover, VTX resulted in significant increase in the levels of urea, creatinine, uric acid, blood urea nitrogen (BUN), kidney injury marker (KIM‐1), neutrophil gelatinase‐associated lipocalin (NGAL), N‐acetyl glucosamine (NAG), cystatin C, and Endothelin‐1 alongside decreased creatinine clearance. In addition, the levels of nuclear factor kappa‐B (NF‐κB), tumor necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β), interleukin‐6 (IL‐6), and cyclooxygenase‐2 (COX‐2) were increased following the administration of VTX. Furthermore, 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 upregulated while the concentrations of B‐cell lymphoma 2 (Bcl‐2) were suppressed after VTX intoxication. Besides, VTX exposure induced renal histopathological alterations including glomerular degeneration, tubular necrosis, inflammatory infiltration, vascular congestion, vacuolization of the tubular epithelial cells, tubular dilatation, interstitial oedema and marked disruption of renal architecture in a dose‐dependent manner. In silico analysis showed favorable interactions among VTX with TLR4 and STAT1, thereby predicting their involvement as molecular targets in VTX‐induced nephrotoxicity. These results show that subacute exposure to VTX causes nephrotoxicity associated with dysregulation of TLR4/MyD88 axis, IFN‐γ pathway, oxidative stress, inflammatory and apoptotic profile of renal tissues.