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 patients with ORG, 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 demonstrated the enhanced endocytosis of lipids by podocytes from patients with ORG. This response was associated with decreased expression of phosphatase and tensin homolog (PTEN). In vitro silencing of PTEN promoted the endocytosis of low-density lipoprotein in mouse podocytes. Conversely, overexpression of PTEN inhibited 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, inhibition of PTEN resulted in the phosphorylation and inactivation of cofilin-1, leading to F-actin formation that enhanced the endocytosis of lipoproteins in podocytes. When hyperlipidemia was induced in mice with podocyte-specific deletion of PTEN, these mice recapitulated the major pathophysiological features of ORG. Thus, PTEN downregulation in podocytes may contribute to the pathogenesis of ORG.
Keywords: cofilin-1; endocytosis; obesity-related nephropathy; phosphatase and tensin homolog; podocytes.