Kidney Week

Abstract: TH-OR007

Mapping Per- and Polyfluoroalkyl Substances-Induced Kidney Injury with Spatial and Single-Nucleus Transcriptomics

Session Information

• Advances in Renal Pathology and Laboratory Medicine
  October 22, 2026 | Location: Room 605, Convention Center
  Abstract Time: 05:30 PM - 05:40 PM

Category: Pathology and Lab Medicine

• 1700 Pathology and Lab Medicine

Authors

• Kowal, Thomas, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Thomas Kowal, PhD

• Wang, Hongxu, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Hongxu Wang, MS

• Zhang, Lu, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Lu Zhang

• Street, Kelly, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Kelly Street, PhD

• Jia, Qiran, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Qiran Jia, MS

• Khayatkhoei, Mahyar, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Mahyar Khayatkhoei, PhD

• Goodrich, Jesse Allen, University of Southern California Keck School of Medicine, Los Angeles, California, United States

Jesse Allen Goodrich, PhD

• Nelson, Jonathan W., University of Southern California Keck School of Medicine, Los Angeles, California, United States

Jonathan W. Nelson, PhD

Background

Per- and polyfluoroalkyl substances (PFAS) are pervasive toxic chemicals that accumulate in the kidney and may increase tubular injury. PFAS are known from hepatic exposure studies as PPARa activators that trigger oxidative stress response and ferroptosis, but unexplored in the kidney. Given the central role of proximal tubules (PT) in clearance of nephrotoxins, we expected to detect PT-targeted cellular dysfunction driven by PFAS exposure.

Methods

Two-month-old wild type mice were fed a diet compounded with vehicle or PFAS (1 mg/kg or 10 mg/kg) for 21 days. Kidneys were collected for spatial transcriptomics (10X Xenium platform with a kidney-focused 5,106-gene panel) and single-nucleus RNA sequencing (snRNAseq). PFAS-induced kidney injury was then evaluated with dissociated and spatial transcriptomics, focusing primarily on PT cells in the analysis.

Results

We observed concordance in the magnitude and direction of key genes across the Xenium and snRNAseq platforms. Detected DEGs were consistent with the induction of similar responses as have been observed for PFAS in the liver, including PPARa activation and oxidative stress (Cyp4a14, Ehhadh, Gpx3) and a ferroptotic response (Ftl1, Fth1). The transcriptional program also revealed a suppressed immune response (Stat1, Iigp1) and impaired maintenance of tubular cell structural integrity (Gucy1a1, Aacs).

Spatial transcriptomics contextualized the PFAS-induced injury by revealing regions of low transcript density predominantly near PT cells. We observed, up-regulation of oxidative stress response and structural repair genes (Gstp1, Neat1, Mdk) and down-regulation of structural integrity-related genes (Lmna, Frs2, Cdipt) in PTs localized to the deserts relative to PTs in the rest of the tissue, suggesting that these are focal sites of enhanced PT injury.

Conclusion

Together, these analyses reveal a spatially contextualized, dose-responsive oxidative, ferroptotic, and immunosuppressive response in the kidney following systemic PFAS exposure, similar to reported effects in the liver. The increased sensitivity and spatial resolution of localized sites of PT injury illustrate the unique advantages of applying both dissociated and spatial transcriptomics in nephrotoxicity research.

Funding

• NIDDK Support