Kidney Week

Abstract: FR-PO778

Cathepsin B Alleviates the Development of Focal Segmental Glomerulosclerosis

Session Information

• Glomerular Diseases: Mechanisms and Podocyte Biology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Theilig, Franziska, CAU Kiel Institute of Anatomy, Kiel, Germany

Franziska Theilig, MD

• Trujillo Miranda, Mairon, CAU Kiel Institute of Anatomy, Kiel, Germany

Mairon Trujillo Miranda

• Promnitz, Jessica, CAU Kiel Institute of Anatomy, Kiel, Germany

Jessica Promnitz

• Saudenova, Makhabbat, CAU Kiel Institute of Anatomy, Kiel, Germany

Makhabbat Saudenova

• Westermann, Magdalena, CAU Kiel Institute of Anatomy, Kiel, Germany

Magdalena Westermann

• Mollet, Geraldine, Université Paris Cité, Laboratory of Hereditary Kidney Diseases, Inserm UMR1163, Imagine Institute, Paris, France

Geraldine Mollet, PhD

• Riebeling, Theresa, University Clinic Schleswig-Holstein, Department of Nephrology, Kiel, Germany

Theresa Riebeling, MSc, PhD

• Krautwald, Stefan, University Clinic Schleswig-Holstein, Department of Nephrology, Kiel, Germany

Stefan Krautwald, PhD

• Demir, Fatih, Aarhus University Department of Biomedicine, Aarhus, Denmark

Fatih Demir

• Rinschen, Markus M., Aarhus University Department of Biomedicine, Aarhus, Denmark

Markus M. Rinschen, MD

• Dahlke, Eileen, CAU Kiel Institute of Anatomy, Kiel, Germany

Eileen Dahlke, PhD

Background

Focal segmental Glomerulosclerosis (FSGS) is one of the most typical histopathological causes of glomerulopathy affecting primarily the podocyte. Lysosomes are responsible for the degradation of molecules via hydrolytic enzymes, such as cathepsin B (CatB) and may serve as a platform mediating cellular signaling in podocytes. Additionally, podocyte stress is associated with lysosome dysfunction. In this study we aim to explore the role of CatB in the progression of podocyte dysfunction to FSGS.

Methods

Podocyte-specific NPHS2 deleted mouse model (Pod^CreNPHS2^flox) leading to FSGS development were used and cross-bred for additional podocyte-specific or complete CatB deletion. Renal function parameter analysis, histolmorphological analysis, transmission electron microscopy (TEM) imaging and immunohistochemistry (IHC) were performed after 3 weeks of induction. Isolated glomeruli from the mouse models were analyzed by proteomic/N-terminomic analysis.

Results

Renal function parameter demonstrated higher BUN, plasma creatinine levels and proteinuria in Pod^CreNPHS2^flox compared to Pod^CreNPHS2^flox with CatB deletion and to control. Morphological analysis revealed higher glomerular and tubulointerstitial damage score in PodCreNPHS2flox compared to Pod^CreNPHS2^flox with CatB deletion and to control. IHC revealed an increased expression of TFEB, LAMP1 and galectin 3 in Pod^CreNPHS2^flox which was attenuated by additional CatB deletion. TEM analysis demonstrated a significant increase in mitochondrial and podocyte injury in Pod^CreNPHS2^flox compared to control and mice with additional CatB deletion which corroborates with higher processing of various mitochondrial proteins identified by N-terminomic analysis. Inflammasome activation was strongly induced in Pod^CreNPHS2^flox compared to control and tom mice with additional CatB deletion.

Conclusion

CatB deletion prevents the development of FSGS, keeping the Pod^CreNPHS2^flox mouse model to a minimal change disease. In FSGS progression, CatB induces inflammasome activation and spreading and mitochondria dysfunction, showing that CatB may be an option to target FSGS treatment.

Funding

• Government Support – Non-U.S.