Oral Subchronic Exposure to Silver Nanoparticles Causes Renal Damage Through Apoptotic Impairment and Necrotic Cell Death

Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials. Following oral exposure, AgNPs can accumulate in various organs including kidneys where they show gender specific accumulation. There is limited information on their effect on renal system following long-term animal exposure especially at the ultramicroscopic and molecular level. In this study, we have assessed the effect of 60 days oral AgNPs treatment on kidneys of female Wistar rats at doses of 50 ppm and 200 ppm that are below previously reported lowest observed adverse effect level (LOAEL). AgNPs treatment led to decrease in kidney weight and some loss of renal function as seen by increased levels of serum creatinine and early toxicity markers such as KIM-1, clusterin and osteopontin. We also observed significant mitochondrial damage, loss of brush border membranes, pronounced swelling of podocytes and degeneration of their foot processes using transmission electron microscopy (TEM). These symptoms are similar to those seen in nephrotic syndrome and 'Minimal change disease' of kidney where few changes are visible under light microscopy but significant ultrastructural damage is observed. Prolonged treatment of AgNPs also led to the activation of cell proliferative, survival and proinflammatory factors (Akt/mTOR, JNK/Stat and Erk/NF-κB pathways and IL1β, MIP2, IFN-γ, TNF-α and RANTES) and dysfunction of normal apoptotic pathway. Our study shows how long term AgNPs exposure may promote ultrastructural damage to kidney causing inflammation and expression of cell survival factors. These changes, in the long term, could lead to inhibition of the beneficial apoptotic pathway and promotion of necrotic cell death in kidneys.