Abstract: TH-PO0832
Characterizing the Role of Tubular Albumin Endocytosis in Renal Per- and Polyfluoroalkyl Substances Reabsorption: A Translational Approach
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Sharkey, Hannah, University of Southern California, Los Angeles, California, United States
- Burfeind, Kevin G., Oregon Health & Science University, Portland, Oregon, United States
- Kahwaji, Mariah M., University of Southern California, Los Angeles, California, United States
- Chen, Brianna, University of Southern California, Los Angeles, California, United States
- Wang, Hongxu, University of Southern California, Los Angeles, California, United States
- Kowal, Thomas, University of Southern California, Los Angeles, California, United States
- Paik, Adelynn, University of Southern California, Los Angeles, California, United States
- Bjornstad, Petter, University of Washington School of Medicine, Seattle, Washington, United States
- Conti, David J., Colorado School of Public Health, Aurora, Colorado, United States
- Andra, Syam S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Petrick, Lauren, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Wright, Robert O., Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Achaintre, David, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Le Marchand, Loic, University of Hawai'i Cancer Center, Honolulu, Hawaii, United States
- Mancuso, Nicholas, University of Southern California, Los Angeles, California, United States
- Setiawan, Veronica Wendy, University of Southern California, Los Angeles, California, United States
- Nelson, Jonathan W., University of Southern California, Los Angeles, California, United States
- Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
- Goodrich, Jesse Allen, University of Southern California, Los Angeles, California, United States
Background
Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous environmental chemicals that accumulate in the kidney and are linked to risk of chronic kidney disease. PFAS exhibit long biological half-lives; Perfluorooctanesulfonic acid (PFOS), one of the most highly detected PFAS, has a half-life of 3+ years. One hypothesis for this longevity is that several PFAS are predominately (>99%) bound to albumin in circulation, and that efficient proximal tubular reabsorption of the small amounts of filtered albumin via megalin and cubilin (encoded by LRP2 and CUBN) may effectively eliminate renal PFAS clearance. We aimed to characterize the role of LRP2- and CUBN-mediated tubular albumin endocytosis in driving PFAS retention by combining genetic epidemiology approaches with an experimental model of tubular proteinuria.
Methods
Plasma PFAS concentrations were quantified using liquid chromatography with high-resolution mass-spectrometry. To examine whether CUBN and LRP2 gene expression altered serum PFOS concentrations, we conducted a two-sample Mendelian Randomization (MR) analysis using Egger regression, adjusting for linkage disequilibrium. Tubular expression quantitative trait loci (eQTLs) were identified from NephQTL2, and associations between these instrumental SNPs and PFOS were tested in the Multiethnic Cohort (MEC; n = 4873). We experimentally validated these findings using an Lrp2 knockout mouse model. Knockout mice and controls were given a single dose of PFOS via oral gavage; clearance was tracked for 7 days and renal PFOS concentrations were compared at day 7.
Results
In the MEC, 7 SNPs in CUBN were associated with statistically significant differences in PFOS levels at a genome-wide significance threshold of 5 x 10-8. MR analysis suggested that genetically determined differences in tubular CUBN gene expression drove differences in PFOS concentrations (p<0.001). Further, inducing tubular albuminuria in mice via Lrp2 knockout resulted in 30.4% (95% CI -48.4, -6.1) lower kidney PFOS concentrations and 296% (95% CI 50.65, 880.0) higher urine clearance of PFOS after 7 days.
Conclusion
Our findings suggest that tubular albuminuria can increase PFOS clearance, challenging the prevailing theory that organic anion transporters are the primary mechanisms of renal PFAS retention.
Funding
- Other NIH Support