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Abstract: TH-PO1096

Bag3 as Potential Mechanoprotector in Renal Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Plagmann, Ingo, University of Cologne, Cologne, Germany
  • Rinschen, Markus M., The Scripps Research Institute, La Jolla, United States
  • Heinlein, Karim, University of Cologne, Cologne, Germany
  • Degenhardt, Jan Christoph, University of Cologne, Cologne, Germany
  • Unnersjö-Jess, David, KTH Royal Institute of Technology, Stockholm, Sweden
  • Schermer, Bernhard, University of Cologne, Cologne, Germany
  • Benzing, Thomas, University of Cologne, Cologne, Germany
Background

Loss of podocytes in the course of glomerular diseases leads to glomerulosclerosis and progressive kidney disease. Due to their exposed location on the outside of the glomerular basement membrane podocytes are subjected to extensive mechanical strain by perfusion and filtration. These forces are even higher in disease states such as diabetic nephropathy. Overtaxing adaptive mechanisms causes podocyte detachment which in turn increases the mechanical stress for remaining podocytes. The precise mechanisms involved in this vicious circle are yet insufficiently defined.
Bag3 is an important mechanoprotector protein in mechanically strained tissues. It replaces mechanically unfolded proteins by chaperone-assisted-autophagy (CASA) and regulates proteins like Filamin A and Synaptopodin, that play a central role in podocyte biology. Above all Bag3 is an important player in diabetic nephropathy in a mouse model. All this brings Bag3 in a prime position as a candidate mediator of mechanical stress protection in podocytes.

Methods

We examined podocytes by immunofluorescence, super-resolution-microscopy and mass-spectrometry for Bag3 expression and characterized the Bag3 interactome using immunoprecipitation. Mechanical stress was induced by stiff matrices and cyclic stretch. The role of Bag3 in vivo is being evaluated in two different mouse lines (Bag3.P209L mutation and a conditional knockout).

Results

Bag3 expression can be shown inside the glomerulus with podocytes displaying a Bag3 enrichment in mass-spectrometry data. Furthermore Bag3 expression is regulated by mechanical clues in podocyte cell lines and first interactome results point towards a function at the liquid stress-granula interface. Preliminary analyses of the myopathy causing mutation Bag3.P209L revealed a mild albuminuria starting at an age of 8-12 weeks in a whole-body overexpression mouse line.

Conclusion

Our findings point towards an important role of Bag3 and chaperone-assisted-selective-autophagy in podocytes and their mechanical stress protection. Bag3 localization at the slit diaphragm in STED-imaging further corroborates this hypothesis. Further studies based on two podocyte specific mouse lines (Bag3 mutation and conditional knockout) are currently ongoing to understand the role of podocyte-Bag3 in vivo under healthy conditions and in glomerular disease.

Funding

  • Government Support - Non-U.S.