Per- and Polyfluoroalkyl Substances Induces Salt-Sensitive Hypertension by Upregulating Epithelial Sodium Channel -...

Area of Science:

• Environmental Health
• Toxicology
• Renal Physiology

Background:

• Per- and polyfluoroalkyl substances (PFAS) are widespread synthetic chemicals linked to hypertension and kidney dysfunction in human studies.
• Causality and mechanisms of PFAS-induced health effects remain unclear.

Purpose of the Study:

• To investigate the causal effects of a mixture of four common PFAS (PFOA, PFOS, PFHxS, PFNA) on blood pressure, salt sensitivity, and kidney injury in mice.
• To elucidate the underlying renal epithelial mechanisms involved in PFAS toxicity.

Main Methods:

• 129S6 mice were exposed to a low or high dose mixture of four PFAS for 3 weeks.
• Blood pressure, salt sensitivity, and renal histology were assessed.
• Single-cell RNA sequencing and Western blotting were used to analyze kidney tissue.

Main Results:

• PFAS exposure induced dose-dependent hypertension and salt sensitivity in male mice, accompanied by glomerulopathy and interstitial fibrosis.
• Kidney transcriptional analysis revealed changes in proximal tubule, thick ascending limb, and collecting duct, impacting cholesterol synthesis, mitochondrial respiration, and transporter activity.
• PFAS increased renal αENaC expression and reduced Nedd4-2 phosphorylation, suggesting impaired ENaC degradation.

Conclusions:

• PFAS exposure causally promotes hypertension, salt sensitivity, and kidney injury in male mice.
• Renal epithelial mechanisms, particularly involving the epithelial sodium channel (ENaC), are implicated in PFAS toxicity.
• These findings support and extend human epidemiological observations on the adverse health effects of PFAS.