Kidney Week

Abstract: TH-PO0420

HTRA1 Impairs Complement Factor H Recruitment by Remodeling Apolipoprotein E (ApoE) and the Glomerular Basement Membrane

Session Information

• Glomerular Diseases: Autoimmune Diseases
  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

• Takayama, Suguru, University of Utah Health, Salt Lake City, Utah, United States

Suguru Takayama, MD, PhD

• Demir, Fatih, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark

Fatih Demir

• Hinckley, Mckinnon, University of Utah Health, Salt Lake City, Utah, United States

Mckinnon Hinckley

• Caza, Tiffany, Arkana Laboratories, Little Rock, Arkansas, United States

Tiffany Caza, MD, PhD

• Liu, Zetao, The Hospital for Sick Children, Toronto, Ontario, Canada

Zetao Liu, PhD

• Licht, Christoph, The Hospital for Sick Children, Toronto, Ontario, Canada

Christoph Licht, MD, FASN

• Beck, Laurence H., Boston Medical Center, Boston, Massachusetts, United States

Laurence H. Beck, MD, PhD

• Rinschen, Markus M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark

Markus M. Rinschen, MD

• Al-Rabadi, Laith, University of Utah Health, Salt Lake City, Utah, United States

Laith Al-Rabadi, MD

Background

Complement activation is common in membranous nephropathy, but it remains unclear how immune deposits in the glomerular basement membrane (GBM) cause complement dysregulation. We recently identified HTRA1 as an autoantigen that accumulates within the GBM. Because CFH recruitment to the GBM depends on heparan sulfate, we asked whether HTRA1 affects CFH regulation directly or by altering the matrix environment required for CFH localization.

Methods

Recombinant ApoE was incubated with active HTRA1 or catalytically inactive HTRA1-S328A under time- and dose-response conditions, followed by immunoblotting. We then repeated these studies using human glomerular extract and GBM-enriched extracellular matrix fractions. CFH and additional complement proteins were tested as potential HTRA1 substrates. Heparin-affinity assays were used to assess binding of HTRA1, ApoE, and CFH to heparan sulfate–like domains. We also tested whether HTRA1 degrades GBM-associated heparan sulfate proteoglycan components, including agrin and perlecan. Alternative pathway activity was assessed using complement activation assays.

Results

HTRA1 caused clear time- and dose-dependent degradation of recombinant ApoE, while inactive HTRA1-S328A had little to no effect. Similar ApoE degradation was seen in human glomerular extract and GBM-enriched matrix fractions, suggesting that this interaction can occur in a glomerular matrix setting. In contrast, CFH and other tested complement proteins were not detectably cleaved by HTRA1. HTRA1 alone also did not activate the alternative pathway in vitro. ApoE interacted with CFH, and both ApoE and CFH bound heparin, supporting the idea that these proteins share dependence on heparan sulfate–rich matrix domains for localization. HTRA1 also degraded GBM-associated matrix proteins, including agrin and perlecan, suggesting that it may reduce CFH recruitment by modifying both CFH-anchoring cofactors and the GBM scaffold itself.

Conclusion

These findings suggest that HTRA1 does not drive complement activation by directly cleaving CFH or other complement proteins. Instead, HTRA1 may create a GBM environment that is less able to retain CFH by degrading ApoE and heparan sulfate–associated matrix components. This provides a plausible mechanism linking HTRA1 accumulation, GBM remodeling, and alternative pathway activation in HTRA1-associated membranous nephropathy.

Funding

• NIDDK Support