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Kidney Week

Abstract: SA-OR055

Mechanism of Albuminuria in Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Butt, Linus, University Hospital of Cologne, Cologne, Germany
  • Unnersjö-Jess, David, Royal Institute of Technology, Solna, Sweden
  • Höhne, Martin, University Hospital Cologne, Cologne, Germany
  • Rinschen, Markus M., The Scripps Research Institute, La Jolla, California, United States
  • Brismar, Hjalmar, Royal Institute of Technology, Solna, Sweden
  • Schermer, Bernhard, University Hospital Cologne, Cologne, Germany
  • Benzing, Thomas, University of Cologne, Köln, Germany
Background

Albuminuria is regarded as the most important predictor of progression in a variety of glomerular diseases including Focal-Segmental Glomerulosclerosis (FSGS). Investigating the events causing the occurrence of albuminuria is of utmost importance for future preventive and therapeutic strategies.

Methods

NPHS2 encodes for the PHB-domain protein podocin and is the most frequently mutated gene in patients with a Steroid-Resistant Nephrotic Syndrome (SRNS) and FSGS. Using CRISPR/Cas9 mediated genome editing, we inserted two separate point mutations into the murine Nphs2 gene which, in combination, cause late-onset SRNS and FSGS in patients. Disease occurrence and development was assessed using histological and clinical parameters. In addition, changes in the podocytes' foot process morphology and slit diaphragm integrity were investigated using Stimulation Emission Depletion (STED) microscopy.

Results

Compound-heterozygous mice exhibit a mild-onset phenotype reminiscent of patients with the equivalent mutations. FSGS lesions are detectable in young adult mice and lead to end-stage renal disease starting as early as 15-20 weeks. Investigation of the podocyte and the slit diaphragm with STED microscopy showed several distinctive morphological changes like foot process length and width and slit diaphragm length which progress over time. Strikingly, some of the changes correlate tightly with albuminuria and precede the overt onset of disease, podocyte loss and glomerular scarring. We provide evidence that shortening of the slit diaphragm reduces the podocytes’ ability to counteract the hydrostatic pressure within the capillaries. This leads to a decreased compression of the glomerular basement membrane (GBM) which results in albuminuria.

Conclusion

We have generated a new mouse model that mimicks the course of disease in patients with a hereditary late-onset SRNS and FSGS. This new mouse model allows the investigation of early disease stages prior to the onset of podocyte depletion, glomerular scarring and massive proteinuria. Based on our data of foot process morphology and slit diaphragm integrity, glomerular filtration rate and albuminuria, we developed a model that attributes the occurrence of albuminuria to a decreased compression of the GBM. In addition, the proposed mechanism of albuminuria can be adapted to other albuminuric pathologies.