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Abstract: SA-PO998

PIK3CA Activation in Extracapillary Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Yamaguchi, Junna, Institut Necker-Enfants Malades, Paris, Île-de-France, France
  • Isnard, Pierre, Institut Necker-Enfants Malades, Paris, Île-de-France, France
  • Hoguin, Clément, Institut Necker-Enfants Malades, Paris, Île-de-France, France
  • Hummel, Aurelie, Hopital Universitaire Necker-Enfants Malades, Paris, France
  • Canaud, Guillaume, Institut Necker-Enfants Malades, Paris, Île-de-France, France

Group or Team Name

  • Team "Mechanisms and Therapeutic Strategies in Overgrowth Syndromes and Vascular Anomalies."
Background

Extracapillary glomerulonephritis are severe kidney disorders frequently associated with end stage kidney disease. Therapeutic options for these diseases are limited especially due to insufficient understanding of their pathophysiology.

Methods

Following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we used multiple genetically engineered mouse models, single cell RNA sequencing and spatial transcriptomics to unveil the role of PI3K-Akt mTOR pathway in podocyte biology of proliferative glomerulonephritis. Alpelisib, a pharmacological PI3Ka inhibitor, was used to inhibit the pathway.

Results

Podocyte-specific PIK3CA overactivation in mice developed progressive focal segmental glomerulosclerosis with podocyte proliferation, dedifferentiation and inflammation. Alpelisib treatment improved glomerular lesions and kidney function in different models of collapsing glomerulopathy and lupus nephritis by targeting podocytes. In addition, even more importantly and unexpectedly, we uncover that pharmacological inhibition of PI3Ka affects B and T lymphocyte population in lupus nephritis mouse models with reduction in proinflammatory cytokine and auto antibodies production, immunoglobulin and complement deposition. These findings were further confirmed in Human lymphocytes isolated from patients with lupus nephritis.

Conclusion

We demonstrate the crucial role played by PI3Ka for proliferative glomerular diseases and showed for the first time that alpelisib represents a promising therapeutic acting on both, podocytes and immune compartment.

Funding

  • Private Foundation Support