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Abstract: FR-PO331

Recovering Impaired Cell Adhesion in Cystinosis Podocytes: A New Therapeutic Strategy?

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Berlingerio, Sante Princiero, Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Flanders, Belgium
  • Tassinari, Sarah, Universita degli Studi di Torino, Torino, Piemonte, Italy
  • Bondue, Tjessa, Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Flanders, Belgium
  • Fransen, Marc, Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Flanders, Belgium
  • Van den heuvel, Lambertus P.W.J., Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Flanders, Belgium
  • Levtchenko, Elena N., Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven, Leuven, Flanders, Belgium

Group or Team Name

  • Prof. Levtchenko
Background

Cystinosis is a rare, incurable autosomal recessive storage kidney disease caused by mutations in CTNS gene, which encodes the cystine transporter cystinosin and leads to lysosomal cystine accumulation in all the body. In addition to proximal tubular cells, cystinosis also affects the glomerulus since podocytes are lost into urine leading to proteinuria and kidney failure. Cysteamine, the current treatment, decrease cystine accumulation but does not reverse proximal tubular injury (renal Fanconi syndrome) neither glomerular injury. These evidences suggest that different mechanisms are involved and further studies are necessary to understand the disease in order to develop new therapeutic options.

Methods

Immortalized patient-derived cystinosis and healthy podocytes were used and the results were validated in our newly in-house developed fluorescent CTNS zebrafish larvae model (l-fabp:DBP-eGFP;CTNS). To understand the impaired podocyte functionality, static and dinamic permeability assay, metabolomic analysis (LC-MS), flow cytometry, RT-qPCR, western blot, chemical and dynamic roGFP2 redox-sensing fluorescent probes were used.

Results

Cystinosis podocytes present decreased adhesion and increased permeability caused by an accumulation of mitochondrial ROS. Moreover, they show fragmented mitochondrial network with impaired TCA cycle, energy metabolism and decreased superoxide scavenging SOD2 enzyme. Interestingly, treatment with the mitochondrial superoxide scavenger mitoTEMPO can rescue the impaired adhesion and permeability in vitro and in vivo.

Conclusion

An impaired mitochondrial oxidative stress is a critical feature in cystinosis podocytes and the combinatory treatment of cysteamine with targeted antioxidant improves podocytes adhesion and permeability. Moreover, our developed fluorescent CTNS zebrafish larvae model is a useful high-throughput tool for screening new therapeutic strategies aiming at restoring the kidney functionality in cystinosis.