PIK3R4 as a potential regulator of Kidney Injury Molecule-1-mediated cell signalling in proximal tubule cells
Abstract
Kidney injury molecule-1 (KIM-1) is upregulated on injured renal proximal tubule epithelial cells (PTECs) during acute kidney injury (AKI) and can transform PTECs into semi-professional phagocytes to remove apoptotic cells. KIM-1 also induces autophagy, which facilitates efficient phagocytosis. Currently, KIM-1 signalling contributes to tissue injury or repair remains unclear. We hypothesized that KIM-1 interacts with novel intracellular proteins to regulate cellular processes including autophagy and cell death during tissue injury. Using KIM-1 co-immunoprecipitation and mass spectrometry, we identified the PI3K regulatory subunit 4 (PIK3R4) as a KIM-1-interacting protein. We discovered that KIM-1 stimulation with apoptotic cells increased autophagy. Silencing KIM-1 in PTECs enhanced necrotic cell death and inhibited cell proliferation, which was mediated by PIK3R4. We propose that KIM-1 inhibits PIK3R4-mediated cell proliferation to prevent further exposure to injury. This knowledge may help to develop therapeutic strategies to accelerate renal recovery after AKI by targeting KIM-1 or its interacting proteins.