Protective Role of the Podocyte IL-15 / STAT5 Pathway in Focal Segmental Glomerulosclerosis

Abstract

IntroductionDuring 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. MethodsWe describe STAT5 expression in human kidney biopsies from patients with focal and segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific Stat5 deletion in experimental glomerular diseases. ResultsHere, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. Additionally, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. 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. ConclusionIn conclusion, activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.