Effects of Particulate Matter on CKD: Inflammation, Oxidative Stress, and Fibrosis in an Animal Model

Background: The exposure to particulate matter (PM) is regarded to be associated with respiratory, cardiovascular, and kidney diseases based on epidemiological analysis. However, there are no studies investigating the causative role of PM in the kidney disease. The activation of endoplasmic reticulum (ER) stress, NLRP3 inflammasome, and oxidative stress are the key mechanisms of renal injury. This study is undertaken to explore the effects of artificially manufactured PM (APM) on the kidneys of animal model of CKD, unilateral ureteral obstruction (UUO). Methods: Male Sprague-Dawley rats were divided into four groups: Normal control, APM (5 mg/kg, administration for 3 or 5 times via Intratracheal instillation), UUO, and UUO+APM. BUN, proteinuria, renal histology including macrophage marker ED-1 expression, and the markers of ER stress (GRP78, ATF4, CHOP, and cleaved caspase-1), NLRP3 inflammasome (NLRP3 and ASC), oxidative stress (nitrotyrosine, SOD2, catalase, and GPx1) and renal fibrosis (F4/80, α-SMA, and osteopontin) in the kidneys were analyzed at 9 or 14 days of APM exposure. Results: UUO increased BUN, tubulointerstitial fibrosis, and expression of GRP78, ATF4, CHOP, and NLRP3, ASC, cleaved caspase-1. Markers of renal fibrosis are upregulated with an increased nitrotyrosine and reduced SOD2, catalase, and GPx1 in UUO group. In APM+UUO group, ED-1, GRP78, CHOP expression was increased in 9 and 14 days, and NLRP3, cleaved caspase-1, F4/80, and osteopontin were upregulated in 14 days. In normal rats, APM also increased the expression of ATF4, cleaved caspase-1 and NLRP3 with an imbalance of oxidative stress and increased expression of F4/80 and osteopontin. Conclusion: Exposure to APM resulted in an enhanced expression of markers of renal inflammation, ER stress, oxidative stress, NLRP3 inflammasome, and fibrosis in both normal and UUO rat models. These findings suggest a potential causative role of PM in kidney disease in subject with normal renal function and CKD. Funding: Government Support – Non-U.S.