Downregulation of PTEN promotes podocyte endocytosis of lipids aggravating obesity-related glomerulopathy

Y Shi, etc
American Journal of Physiology-Renal Physiology, 2019


With the increasing prevalence of obesity in adults worldwide, the incidence of obesity-related glomerulopathy (ORG) has increased yearly, becoming one of the leading causes of end-stage renal disease. Studies have demonstrated significant correlations between hyperlipidemia and impaired renal function in ORG patients, indicating that hyperlipidemia causes damage in kidney cells. In podocytes, the endocytosis of lipids triggers an intracellular oxidative stress response that disrupts cellular integrity, resulting in proteinuria and glomerular sclerosis. However, the specific molecular mechanisms through which podocytes endocytose lipids remain unclear. Here, we demonstrate the enhanced endocytosis of lipids by podocytes from patients with ORG. This response is associated with the decreased expression of phosphatase and tensin homolog (PTEN). The in vitro silencing of PTEN promotes the endocytosis of low-density lipoproteins (LDL) in mouse podocytes. Conversely, the overexpression of PTEN inhibits the endocytosis of lipoproteins in podocytes. PTEN directly dephosphorylates and activates the actin depolymerizing factor cofilin-1, leading to depolymerization of filamentous actin (F-actin), which is necessary for endocytosis. Notably, the inhibition of PTEN results in the phosphorylation and inactivation of cofilin-1, leading to an F-actin formation that enhances the endocytosis of lipoproteins in podocytes. When hyperlipidemia is induced in mice with the podocyte-specific deletion of PTEN, these mice recapitulate the major pathophysiologic features of ORG. Thus, PTEN downregulation in podocytes may contribute to the pathogenesis of ORG.

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Journal
American Journal of Physiology-Renal Physiology
Year
2019
Page
doi: 10.1152/ajprenal.00392.2019
Institute
The Affiliated People's Hospital of Shanxi Medical University