PTEN/YAP Mediated Lipid Accumulation in Podocytes Contributes to Glomerulosclerosis

Background: 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 mice and podocyte-specific PTEN knockin mice were 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. Findings: We revealed that partial deletion of PTEN increased lipid accumulation and fibrotic proteins deposition in glomeruli segmentally, and boosted albuminuria in glomerulosclerosis mouse model. Conversely, podocyte-specific overexpression of PTEN induced a marked alleviation in lipid retention in podocytes, albuminuria, and glomerulosclerosis. In cultured podocytes, PTEN was down-regulated by ox-LDL. Overexpression of PTEN reduced endocytic ox-LDL via down-regulating scavenger receptor A (SR-A), decreased intracellular cholesterol content, and thus prevented podocytes from lipid overload. In contrast, inhibition of PTEN aggravated podocytes damage due to more lipid accumulation. Mechanistically, we identified PTEN as a regulator of SR-A by dephosphorylating its nuclear transcription factor, yes-associated protein (YAP), at Ser127 in cytoplasm of ox-LDL treated podocytes. Interpretation: 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. Funding: This study was supported by the National Natural Science Foundation Committee of China and GDUPS. Declaration of Interest: None. Ethical Approval: All animal studies were carried out with the approval of the animal care and use committee of Guangdong General Hospital. All human studies were performed with the approval of the Ethics Committee of Guangdong General Hospital, and written informed consent was obtained from the patients.