Podocyte Lipotoxicity in CKD

Abstract

CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.

Keywords: basic science; chronic kidney disease; lipid accumulation; podocyte lipotoxicity.

Figure 1.

Increased Lipid accumulation in Alport Podocytes. Representative images of BODIPY staining demonstrate increased lipid accumulation in cultured, immortalized Alport podocytes from the Col4A3KO mice (a mouse model for Alport syndrome), compared with wild-type podocytes cultured from the wild-type mice.

Figure 2.

Increased CD36 mediated FFA uptake and decreased ABCA1 expression mediated reduced cholesterol efflux lead to increased lipid accumulation and cause podocyte injury. Discoidin domain receptor 1 (DDR1) interacts with CD36 and induces CD36 activity. Increased CD36 activity in CKD mediates increased free fatty acid (FFA) uptake and triglyceride (TG) accumulation. Increased FFA uptake and TG lipolysis cause intracellular FFA overload to mitochondria, resulting in mitochondrial dysfunction. Cholesterol uptake from circulating LDL occurs via the LDL receptor. Esterified cholesterol accumulates in lipid droplets together with TGs. Decreased expression of ATP-binding cassette A1 (ABCA1)in podocytes in the setting of CKD leads to cholesterol accumulation, causing inefficient formation of the oxidative phosphorylation (OXPHOS) complex and increased oxidized cardiolipin accumulation in mitochondria, which leads to production of reactive oxygen species (ROS) and podocyte injury. CE, cholesteryl ester.