Exposure to Per- and Polyfluoroalkyl Substances (PFAS) Induces Hypertension Via Arginase1-mediated Endothelial Dysfunction

Per- and polyfluoroalkyl substances (PFAS) are a large class of environmental toxicants found in the plasma of 98% of Americans and 45% of US drinking water samples. Humans are primarily exposed through ingestion of PFAS-contaminated food and water, but occupational exposures in firefighters, fluorochemicals workers and other high-risk populations often result in much greater levels of serum PFAS than that of the general public. PFAS exposure is associated with hypertension and kidney dysfunction in epidemiological studies, but the causal effect has not been established. We sought to investigate the effects of a mixture of 4 PFAS species most abundant in human blood (Post CM, et al. J Immunotoxicol. 2024;21:2340495), at exposure levels observed in humans, on blood pressure, salt sensitivity, and renal injury in 129S6 mice. Chronic PFAS exposure in drinking water for 3 weeks increased blood pressure in 129S6 mice on a normal salt diet in a dose dependent manner. When switched to a 4% high salt diet, PFAS-exposed mice compared to control mice exhibited exaggerated salt sensitive hypertension with a simultaneous decline in glomerular filtration rate (GFR). The hemodynamic derangements in PFAS-exposed mice were accompanied by an impairment of acetylcholine-induced, but not sodium nitroprusside-induced, vasodilation in renal resistance vessels, suggesting that endothelium-dependent dilatory dysfunction may have restricted renal perfusion during salt loading (Wu J et al. Cardiovasc Res 2021;117:308-319). Whole kidney proteomics and quantitative PCR analysis of renal cortex revealed that PFAS dose-dependently increased the protein and mRNA of arginase 1, which inhibits eNOS-dependent nitric oxide production by competing for the common substrate L-arginine. Pharmacological inhibition of arginases corrected PFAS-induced endothelial dysfunction in renal microvessels, strongly implicating a renal hemodynamic mechanism in PFAS-induced renovascular dysfunction and hypertension. The salt sensitive hypertension in PFAS-exposed mice was complicated by marked renovascular inward remodeling and wall thickening as well as striking interstitial fibrosis identified in Masson’s Trichrome Blue and Picro Sirius Red staining, indicative of maladaptive kidney remodeling. Together, our results support a novel pathway involving PFAS-Arginiase1-eNOS in the development of endothelial dysfunction and salt sensitive hypertension. To our knowledge, this is the first mechanistic evidence supporting a causal role of PFAS exposure in the pathogenesis of hypertension, salt sensitivity of blood pressure, and kidney damage. Jing Wu is supported by a NIDDK K01 Award (DK126792) and an AHA Second Early Faculty Independence Award (23SCEFIA1148464). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.