Renal Dysfunction Induced by Sodium <i>p</i>-Perfluorous Nonenoxybenzenesulfonate in Mice: Insights from the Intrinsic Mechanisms of Proteinuria

Chronic kidney disease (CKD), characterized by gradual loss of renal function, may be driven by environmental exposure such as perfluoroalkyl and polyfluoroalkyl substances (PFAS), yet the intrinsic mechanisms are largely unknown. Here, we observed distinct proteinuria in the mice exposed to sodium <i>p</i>-perfluorous nonenoxybenzenesulfonate (OBS), an alternative to perfluorooctanesulfonate. The renal S-adenosylhomocysteine (SAH) level increased due to the decrease in its hydrolase adenosylhomocysteinase (AHCY), and was positively correlated with the observed proteinuria. Consequently, the DNA methylation level was downregulated. Specifically, the promoter methylation of <i>Arap3</i> increased, while the genebody methylation of <i>Tiam1</i> decreased, thereby causing downregulation of their mRNA expressions. This further suppressed the levels of Rho GTPases <i>RhoA</i> and <i>Rac1</i>, which then reduced their downstream genes <i>Pip5k1a</i>, <i>Pip5k1b</i> and <i>Pip5k1c</i>, and eventually inhibited <i>Actn4</i> expression. Consequently, the podocyte cytoskeleton was disrupted, promoting foot process fusion and inducing proteinuria. Overexpression of AHCY in OBS-exposed mice reduced the level of SAH, restored the methylation levels and gene expressions, ameliorated the podocyte injury, and eventually reduced the level of urinary protein. Taken together, inhibition of AHCY was the molecular initiating event of OBS-induced proteinuria, which functioned through the AHCY-SAH-Arap3/Tiam1-RhoA/Rac1-Pip5k1a/Pip5k1b/Pip5k1c-Actn4 axis. This study provides profound insight into the potential risk of PFAS in disrupting renal function and kidney health.