The Contribution of Lipotoxicity to Diabetic Kidney Disease

Abstract

Lipotoxicity is a fundamental pathophysiologic mechanism in diabetes and non-alcoholic fatty liver disease and is now increasingly recognized in diabetic kidney disease (DKD) pathogenesis. This review highlights lipotoxicity pathways in the podocyte and proximal tubule cell, which are arguably the two most critical sites in the nephron for DKD. The discussion focuses on membrane transporters and lipid droplets, which represent potential therapeutic targets, as well as current and developing pharmacologic approaches to reduce renal lipotoxicity.

Keywords: cholesterol esters; diabetic kidney disease; fatty acids; lipid droplets; podocyte; proximal tubule.

Figure 1

Lipotoxicity in the podocyte. Under pathologic (albuminuric) circumstances, fatty acids and cholesterol esters are taken up by separate mechanisms. If the accumulated lipids exceed storage capacity within lipid droplets, toxic metabolites accumulate and lead to reactive oxygen species generation, endoplasmic reticulum stress, and ultimately podocyte cell death. Abbreviations: albumin (Alb), AMP-activated protein kinase (AMPK), ATP-binding cassette A1 (ABCA1), cannabinoid receptor type 1 (CB1), ceramide-1-phosphate (Cer1P), cholesterol ester (CE), endoplasmic reticulum (ER), fatty acid (FA), free fatty acid receptor-1 (FFA1), lipid droplet (LD), low density lipoprotein receptor (LDLR), reactive oxygen species (ROS), acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b).

Figure 2

Lipotoxicity in the proximal tubule cell. Under pathologic (albuminuric) circumustances, fatty acids are taken up by transporters at the basolateral and apical membranes. At the apical surface, fatty acids and albumin dissociate and are transported by separate mechanisms. If the accumulated lipids exceed the capacity to undergo β-oxidation within mitochondria or storage within lipid droplets, toxic fatty acid metabolites (ceramides, diacylglycerols, long-chain acyl-CoAs) cause apoptosis and tubular atrophy. Abbreviations: albumin (Alb), amnionless (Amn), cannabinoid receptor type 1 (CB1), ceramide (Cer), cubilin (Cub), diacylglycerols (DAG), fatty acid (FA), fatty acid transport protein (FATP), kidney injury molecule-1 (KIM-1), lipid droplet (LD), low density lipoprotein receptor (LDLR), long-chain acyl-CoAs (LC-CoA), megalin (Meg).