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Abstract: SA-OR052

A Novel Small Molecule Therapy for Nephrotic Syndrome Caused by a Common Podocin Mutation

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Kuzmuk, Valeryia, Univeristy of Bristol, Bristol, United Kingdom
  • Pranke, Iwona, INSERM U1151, Paris, France
  • Ding, Wen Yi, University of Bristol, Bristol, United Kingdom
  • Mollet, Geraldine, Inserm U1163, Paris, France
  • Antignac, Corinne, Imagine Institute/Laboratory of Hereditary Kidney Diseases, Paris, France
  • Foster, Rebecca R., University of Bristol, Bristol, United Kingdom
  • Coward, Richard, University of Bristol, Bristol, United Kingdom
  • Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
  • Edelman, Aleksander, INSERM U1151, Paris, France
  • Saleem, Moin, University of Bristol, Bristol, United Kingdom

There are currently no targeted therapies for the ever-increasing number of podocyte diseases. Currently, there are over 60 different genetic disorders causing SRNS - the commonest of these by far is that of mutations in the NPHS2 gene encoding podocin. Podocin is a key scaffolding protein of the slit diaphragm essential for intact glomerular filtration. The most frequent podocin mutation in European children is R138Q, causing retention of the protein in the ER.


A conditionally immortalized patient cell line with the R138Q mutation was used to study podocin trafficking and biology and to characterize the nature of R138Q-K8 interaction in podocin’s cell type, the kidney podocyte. A conditional podocin knock-in mice carrying R140Q mutation, the mouse analogue of human R138Q, was created using doxycycline-inducible Cre-recombinase technology allowing to study the effects of the mutation in postnatal life and representing an ideal model for pharmacological studies.


We provide evidence that a protein-protein interaction of misfolded podocin R138Q (but not wt podocin) with the intermediate filament K8 prevents its correct trafficking to the PM. We have also identified a small molecule that interrupts this interaction and rescues mutant protein mis-trafficking. This results in functional rescue of podocin in both human patient R138Q mutant podocyte cell line, and in a mouse inducible knock in model of the R138Q mutation. In the mouse, complete rescue of proteinuria and histological changes are seen, when the molecule is administered at disease induction, and also after proteinuria has commenced (F1).


Altogether, this data provided constitutes the first therapeutic option for NS patients bearing the R138Q mutation.