Stagnation of autophagy: A novel mechanism of renal lipotoxicity

Abstract

Excessive fat intake can lead to cellular injury and inflammation (termed lipotoxicity), but studies on lipid metabolism in the kidney have been scarce. We recently identified a novel mechanism of lipotoxicity in the kidney proximal tubules especially focusing on the effect of lipid overload on lysosomal function and autophagic activity. Lipid overload basically stimulates macroautophagy/autophagy for renovation of the plasma and organelle membranes, which plays an essential role in maintaining the integrity of proximal tubules. However, this autophagic activation is inevitably accompanied with lysosomal stress and consequent downstream suppression of autophagy, which manifest as phospholipid accumulation in the lysosome. Stagnation of autophagy can enhance vulnerability to additional stress such as ischemic injury. Pharmacological correction of phospholipid accumulation that restores autophagic flux will be a novel therapeutic option for obesity-related kidney diseases.