Systemic and renal lipids in kidney disease development and progression

Abstract

Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes.

Keywords: cholesterol; dyslipidemia; kidney disease; lipids; podocytes.

Fig. 1.

Common circulating lipid abnormalities in chronic kidney disease (CKD). Patients with CKD exhibit significant alterations in lipoprotein metabolism. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are involved in the transport of cholesterol. Lecithin cholesterol acyltransferase (LCAT) is a central enzyme in the extracellular metabolism of plasma lipoproteins while triglyceride (TG):HDL-cholesterol ratio might be useful as a predictive value on the onset and progression of CKD over time.

Fig. 2.

Cholesterol homeostasis in podocytes. Cholesterol homeostasis is maintained by several mechanisms, and dysregulation of this homeostasis in podocytes may contribute to kidney disease. Cholesterol uptake from circulating oxidized or unoxidized LDL is mediated via the LDL-receptor or CXCL16 and may cause mitochondrial and endoplasmic reticulum stress. Cholesterol synthesis and metabolism are regulated by several nuclear receptors and transcription factors, including SREB1. Neutral cholesterol accumulates in lipid droplets together with triglycerides that are derived from the uptake and metabolism of free fatty acids primarily via platelet glycoprotein 4 (also known as CD36). These free fatty acids can cause oxidative and endoplasmic reticulum stress based on the degree of saturation. Free cholesterol is transported to the plasma membrane via Niemann-Pick disease, type C1/C2 (NPC1/1/2) for efflux primarily by ATP-binding cassette subfamily A member 1 (ABCA1) or converted by sterol O-acyltransferase 1 (SOAT1) into esterified cholesterol (red pentagons) inside lipid droplets. In conditions of cholesterol deficiency, sterol regulatory element-binding protein 1 (SREBP1) is transported from the endoplasmic reticulum to the Golgi apparatus, where it is cleaved to translocate to the nucleus and initiate cholesterol synthesis. Systemic or locally produced apolipoprotein L-1 (APOL1) might modulate oxidative stress and/or contribute to cholesterol efflux via ABCA1 and ATP-binding cassette subfamily G member 1 (ABCG1) by serving as an HDL acceptor together with apoprotein A-1 (APOA1) and apolipoprotein E (APOE).