1. PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis
- Author
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Yamaguchi, Junna, Isnard, Pierre, Robil, Noemie, de la Grange, Pierre, Hoguin, Clement, Schmitt, Alain, Hummel, Aurelie, Megret, Jerome, Goudin, Nicolas, Luka, Marine, Menager, Mickael M., Masson, Cecile, Zarhrate, Mohammed, Bole-Feysot, Christine, Janiszewska, Michalina, Polyak, Kornelia, Dairou, Julien, Baldassari, Sara, Baulac, Stephanie, Broissand, Christine, Legendre, Christophe, Terzi, Fabiola, and Canaud, Guillaume
- Subjects
Glomerulonephritis -- Care and treatment -- Risk factors -- Development and progression ,Health care industry - Abstract
Proliferative glomerulonephritis is a severe condition that often leads to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of- function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing, and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation, and inflammation. Additionally, we show that alpelisib, a PI3K[alpha] inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3K[alpha] affects B and T lymphocyte populations in lupus nephritis mouse models, with a decrease in the production of proinflammatory cytokines, autoantibodies, and glomerular complement deposition, which are all characteristic features of PI3KO inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3K[alpha] inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3K[alpha] in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system., Introduction PI3K[alpha] is a lipid kinase that is widely expressed in various tissues and plays a crucial role in controlling signaling pathways involved in cell proliferation, motility, survival, and metabolism [...]
- Published
- 2024
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