Differential activation of Nrf2-Keap1 and NF-kB pathway mediates size-dependent nephrotoxicity of PM_0.1, PM_2.5, and...

Air pollution is fourth major cause of death worldwide. Recent evidence suggests that particulate matter (PM) may affect kidneys, and the effect may be size and composition dependent. In this study, PM_0.1, PM_2.5, and PM₁₀ were collected from ambient air and given to BALB/c male mice at 0.25 mg/m³ concentration in whole-body inhalation chamber for 28 days (6 h/day, 5 days/week) to assess their effect on kidney. Physico-chemical characterization of PM particles by SEM, ICP-MS and HPLC showed their various shapes along with the presence of metals and poly aromatic hydrocarbons (PAHs). Following PM exposure, increased serum creatinine levels were observed in animals along with dilated tubules, protein cast deposition, necrosis, immune infiltration, collagen deposition, and shrunken glomeruli in kidney. Immunofluorescence staining showed higher expressions of kidney injury molecule1 (KIM-1), cystatin C, β2 microglobulin (β2M), and alpha smooth muscle actin (α-SMA) and fibronectin, suggesting renal injury and fibrosis. PM exposure also increased malondialdehyde (MDA) content and decreased superoxide dismutase 2 (SOD2) activity, which in turn leads to induction of inflammation. Mechanistically, PM exposure further inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling and induced kelch-like ECH-associated protein 1 (Keap1) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). Interestingly, the effect of PM_2.5 was more severe than PM_0.1 and PM₁₀, leading to higher levels of proinflammatory NF-κB and greater Nrf2 inhibition. Overall, our findings suggested that inhalation exposure to size-segregated PM can cause kidney damage and fibrosis, and PM_2.5 showed higher toxicity than PM_0.1 and PM₁₀.