Metabolism, energetics, and lipid biology in the podocyte - cellular cholesterol-mediated glomerular injury

Abstract

Chronic kidney disease (CKD) is associated with a high risk of death. Dyslipidemia is commonly observed in patients with CKD and is accompanied by a decrease in plasma high-density lipoprotein, and an increase in plasma triglyceride-rich lipoproteins and oxidized lipids. The observation that statins may decrease albuminuria but do not stop the progression of CKD indicates that pathways other than the cholesterol synthesis contribute to cholesterol accumulation in the kidneys of patients with CKD. Recently, it has become clear that increased lipid influx and impaired reverse cholesterol transport can promote glomerulosclerosis, and tubulointerstitial damage. Lipid-rafts are cholesterol-rich membrane domains with important functions in regulating membrane fluidity, membrane protein trafficking, and in the assembly of signaling molecules. In podocytes, which are specialized cells of the glomerulus, they contribute to the spatial organization of the slit diaphragm (SD) under physiological and pathological conditions. The discovery that podocyte-specific proteins such as podocin can bind and recruit cholesterol contributing to the formation of the SD underlines the importance of cholesterol homeostasis in podocytes and suggests cholesterol as an important regulator in the development of proteinuric kidney disease. Cellular cholesterol accumulation due to increased synthesis, influx, or decreased efflux is an emerging concept in podocyte biology. This review will focus on the role of cellular cholesterol accumulation in the pathogenesis of kidney diseases with a focus on glomerular diseases.

Keywords: ABCA1; apolipoprotein; cholesterol; glomerular disease; kidney disease; podocyte; renal disease; reverse cholesterol transport.

Figure 1

Intracellular cholesterol trafficking. The fine regulation of cholesterol homeostasis is maintained via different mechanisms. De novo synthesis (blue) of free cholesterol occurs via the rate-limiting enzyme HMG-CoA reductase (HMGCR) at the endoplasmic reticulum (ER). In the event of a cellular cholesterol deficit, cholesterol influx (green) mediated through APOB-rich lipoproteins and triglyceride-rich (TG-rich) lipoproteins occurs. LDLR/lipoprotein complexes are internalized via endocytosis and transported to the lysosome for degradation resulting in LDL and VLDL remnants, thus releasing free cholesterol. As excess free cholesterol is toxic, it is transported to the plasma membrane via NPC1/2 for efflux by an ABCA1-ApoAI/L1- or ABCG1/8-HDL-mediated mechanism (purple), or it is converted to cholesteryl esters via SOAT1 leading to the formation of cholesterol enriched lipid droplets (red). Cholesteryl esters can be converted back to unesterified (free) cholesterol via NCEH. Cholesterol pathways are regulated on a transcriptional level (gray). During cholesterol deficits, SREBP is transported to the Golgi apparatus and cleaved, allowing its translocation to the nucleus to regulate expression of cholesterol genes.