Pten/yap mediated lipid accumulation in podocytes contributes to glomerulosclerosis

Objectives: Lipid deposition in glomeruli is one of the pathological characteristics of focal segmental glomerulosclerosis (FSGS). We have showed that phosphatase and tensin homolog (PTEN) is down-regulated in podocytes from patients with FSGS. However, the role of PTEN in FSGS is still largely unknown.
Methods:PTEN partial knockout mouse was used to establish a glomerulosclerosis mouse model induced by uninephrectomy and high fat diet. Oxidized low-density lipoprotein (ox-LDL) stimulated mouse podocyte (cell line) was used to explore the pathway involved in PTEN mediated lipid accumulation.
Results: We revealed that PTEN was down-regulated in lipid accumulated podocytes in human FSGS by immunohistochemistry. Partial deletion of PTEN increased lipid accumulation and fibrotic proteins deposition in glomeruli segmentally, and boosted albuminuria in glomerulosclerosis mouse model. The lipid retention regulated by PTEN in ox-LDL treated podocytes was mainly attributed to SR-A mediated lipid influx rather than lipid synthesis and effusion. Mechanistically, we identified that PTEN regulated yes-associated protein (YAP) activity and subcellular localization independent of Hippo pathway, and PTEN directly bound and dephosphorylating YAP at Ser127 in cytoplasm of ox-LDL treated podocytes.
Conclusion: These findings implicate a central role of PTEN in a signaling cascade mediating lipid-loading in podocytes which contributes to glomerulosclerosis, and provide evidence for PTEN/YAP as a target for FSGS therapy.