Kidney Week

Abstract: TH-PO0394

WIPF3 Controls Podocyte Foot Process Architecture in a Murine Albuminuria Model

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Spitz, Dominik, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Dominik Spitz

• Gerstner, Lea, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Lea Gerstner, PhD

• Pichukala, Dineesha, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Dineesha Pichukala, MSc

• Butt, Linus, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Linus Butt, MD, DrMed

• Helmstädter, Martin, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Martin Helmstädter

• Unnersjö-Jess, David, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

David Unnersjö-Jess, PhD

• Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States

Sean Eddy, PhD

• Rogg, Manuel, Institute of Surgical Pathology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Manuel Rogg

• Kayser, Séverine, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Séverine Kayser

• Strauch, Martin, Universitatsklinikum Aachen, Aachen, NRW, Germany

Martin Strauch, PhD

• Tholen, Stefan, Institute of Surgical Pathology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Stefan Tholen, PhD

• Latt, Khun Zaw, University of Michigan, Ann Arbor, Michigan, United States

Khun Zaw Latt, MBBS, PhD

• McCown, Phillip J., University of Michigan, Ann Arbor, Michigan, United States

Phillip J. McCown, MS, PhD

• Milosavljevic, Julian, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Julian Milosavljevic, MD

• Boor, Peter, Universitatsklinikum Aachen, Aachen, NRW, Germany

Peter Boor, MD, PhD

• Schilling, Oliver, Institute of Surgical Pathology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Oliver Schilling

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Kottgen, Michael, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Michael Kottgen, MD

• Walz, Gerd, Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Gerd Walz, MD, DrMed

• Schell, Christoph, Institute of Surgical Pathology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Christoph Schell, MD, PhD

• Kottgen, Anna, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Anna Kottgen, MD, MPH

• Hermle, Tobias F., Renal Division, Department of Medicine, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany

Tobias F. Hermle, MD

Background

The kidney filters vast plasma volumes while retaining proteins such as albumin. Albuminuria is common, but even very mild urinary albumin excretion correlates with increased mortality. The mechanisms underlying mild albuminuria remain largely unclear, and specific animal models are lacking. WIPF3, an actin regulator, emerged as a candidate gene for albuminuria in a genome-wide association study.

Methods

To obtain a podocyte-specific knockout of Wipf3, mice carrying a floxed allele were crossed with NPHS2-Cre transgenic animals. Successful Cre-mediated recombination was confirmed by genotyping, quantitative PCR, and mass spectrometry. Phenotypic characterization was carried out using histology, pathomics, immunofluorescence, and electron microscopy. Gene expression analyses were conducted on kidney biopsy samples from patients enrolled in the NEPTUNE cohort.

Results

Podocyte-specific Wipf3 deletion caused mild albuminuria in mice, recapitulating the human phenotype and confirming the causality of the genetic association. Albuminuria was of glomerular origin but occurred without podocyte loss or foot process effacement. Podocytes were not sensitized for Adriamycin toxicity, suggesting sustained cellular viability. However, foot processes were elongated and thinner in mature animals, causing glomerular capillary dilation and widening of the glomerular basement membrane. Basement membrane proteins, including COL4A5, did not show increased abundance. Thus, albuminuria was likely caused by decompression of the gel-like basement membrane. Albumin injection aggravated albuminuria specifically after Wipf3 knockout, underlining filter dysfunction. In human kidney biopsy samples, the podocyte-specific expression of WIPF3 was diminished across a range of glomerular diseases. In FSGS samples, high level of WIPF3 expression predicted kidney survival.

Conclusion

Wipf3 knockout mice provide a genetic albuminuria model. WIPF3 regulates podocyte morphology, and albuminuria following its deletion results from a dysfunctional architecture of the filtration barrier. The association of higher WIPF3 expression with improved kidney survival in human FSGS could imply a broader role in proteinuric kidney disease.

Funding

• Government Support – Non-U.S.