Kidney lipid metabolism: impact on pediatric kidney diseases and modulation by early-life nutrition

Abstract

Our review summarizes and evaluates the current state of knowledge on lipid metabolism in relation to the pathomechanisms of kidney disease with a focus on common pediatric kidney diseases. In addition, we discuss how nutrition in early childhood can alter kidney development and permanently shape kidney lipid and protein metabolism, which in turn affects kidney health and disease throughout life. Comprehensive integrated lipidomics and proteomics network analyses are becoming increasingly available and offer exciting new insights into metabolic signatures. Lipid accumulation, lipid peroxidation, oxidative stress, and dysregulated pro-inflammatory lipid mediator signaling have been identified as important mechanisms influencing the progression of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease, and acute kidney injury. We outline key features of metabolic homeostasis and lipid metabolic physiology in renal cells and discuss pathophysiological aspects in the pediatric context. On the one hand, special vulnerabilities such as reduced antioxidant capacity in neonates must be considered. On the other hand, there is a unique window of opportunity during kidney development, as nutrition in early life influences the composition of cellular phospholipid membranes in the growing kidney and thus affects local signaling pathways far beyond the growth phase.

Keywords: Antioxidants; Children; Early-life nutrition; Kidney lipid metabolism; Lipidomics; Oxidative stress.

A higher resolution version of the Graphical abstract is available as Supplementary information

Fig. 1

An overview of the lipid classes and associated pathways and categories in kidney diseases. SFAs, saturated fatty acids; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; FA, fatty acids; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PI, phosphatidylinositol; PG, phosphatidylglycerol, SM, sphingomyelin, EET, epoxyeicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid. Created with BioRender.com

Fig. 2

Receptors and transport proteins involved in lipid uptake of glomerular and tubular cells. TSP-1, thrombospondin 1; GPR43, G protein-coupled receptor 43; FA, fatty acids; NLRP3, NLR family pyrin domain containing 3; FATP4, fatty acid transport protein 4; CXCL16, scavenger receptor for phosphatidylserine, and oxidized low-density lipoprotein. Created with BioRender.com

Fig. 3

Roles of 20-HETE in different glomerular cell types. Activation of 20-HETE due to increased CYP-mediated AA metabolism can lead to A endothelial dysfunction, B oxidative stress and apoptosis, as well as C vasoconstriction; D paracrine signaling could be of major importance. AA, arachidonic acid; ACE, angiotensin converting enzyme; ARC, arachidonate-regulated calcium channels; CYP, cytochrome P450; CYP4A12, cytochrome P450 A12; c-Src, tyrosinkinase Src; EGFR, epidermal growth factor receptor; GIT1, ARF GTPase-activating protein; Gluc, glucose; GPR75, G-protein coupled receptor 75; 20-HETE, 20-hydroxyeicosatetraenoic acid; InsR, insulin receptor; MLCK, myosin light-chain kinase, PKCα, protein kinase alpha; PLA2, phospholipase A2; ROS, reactive oxygen species; TRPC6, transient receptor potential 6. Created with BioRender.com