#6883 PROTECTIVE ROLE OF THE PODOCYTE IL-15 / STAT5 PATHWAY IN EXPERIMENTAL FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS

Abstract

Abstract Background and Aims During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently detailed in intrinsic kidney cells. We previously evidenced a protective role for a podocyte-expressed immune receptor such as the common gamma chain (ΓC) during glomerulonephritis (1). We also found that STAT5, a transcriptional factor classically described and activated downstream ΓC in T cells is upregulated in podocytes during glomerulonephritis. Method Using a mice model with a podocyte-specific deletion of Stat5, we analyzed the role of STAT5 in two experimental models of glomerular diseases. Results Here, we show, for the first time, that STAT5 is activated in human podocytes in focal and segmental glomerulosclerosis (FSGS). Additionally, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS (Figure 1). This could be due, at least in part, to an inhibition of autophagic flux and an alteration of mitochondrial function. Finally, Interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes. Conclusion In conclusion, activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.