Silica - A trace geogenic element with emerging nephrotoxic potential

Silica is a trace-geogenic compound with limited-bioavailability. It inflicts health-perils like pulmonary-silicosis and chronic kidney disease (CKD), when available via anthropogenic-disturbances. Amidst silica-imposed pathologies, pulmonary toxicological-mechanisms are well-described, ignoring the renal-pathophysiological mechanisms. Hence, the present-study aimed to elucidate cellular-cum-molecular toxicological-mechanisms underlying silica-induced renal-pathology in-vitro. Various toxicity-assessments were used to study effects of silica on the physiological-functions of HK-cells (human-kidney proximal-tubular cells - the toxin's prime target) on chronic (1-7 days) sub-toxic (80 mg/L) and toxic (100-120 mg/L) dosing. Results depicted that silica triggered dose-cum-time dependent cytotoxicity/cell-death (MTT-assay) that significantly increased on long-term dosing with >= 100mg/L silica; establishing the nephrotoxic-potential of this dose. Contrarily, insignificant cell-death on sub-toxic (80 mg/L) dosing was attributed to rapid intracellular toxin-clearance at lower-doses preventing toxic-effects. The proximal-tubular (HK-cells) cytotoxicity was found to be primarily mediated by silica-triggered incessant oxidative-stress (elevated ROS). This enhanced ROS inflicted severe inflammation and subsequent fibrosis, evident from increased pro-inflammatory-cum-fibrogenic cytokines generation (IL-1 beta, IL-2, IL-6, TNF-alpha and TGF-beta). Simultaneously, ROS induced persistent DNA-damage (Comet-assay) that stimulated G2/M arrest for p53-mediated damage-repair, aided by checkpoint-promoter (Chk1) activation and mitotic-inducers (i.e. Cdc-25, Cdk1, cyclinB1) inhibition. However, DNA-injuries surpassed the cellular-repair, which provoked the p53-gene to induce mitochondrial-mediated apoptotic cell-death via activation of Bax, cytochrome-c and caspase-cascade (9/3). This persistent apoptotic cell-death and simultaneous incessant inflammation culminated in the development of tubular-atrophy and fibrosis, the major pathological-manifestations of CKD. These findings provided novel-insights into the pathological-mechanisms (cellular and molecular) of silica-induced CKD, inflicted on chronic toxic-dosing (>= 100 mg/L). Thereby, encouraging the development of therapeutic-strategies (e.g. anti-oxidant treatment) for specific molecular-targets (e.g. ROS) to retard silica-induced CKD-progression, for reduction in the global-CKD burden. (C) 2018 Elsevier B.V. All rights reserved.