Rotten to the Cortex: Ceramide-Mediated Lipotoxicity in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a prevalent and progressive comorbidity of diabetes mellitus that increases one’s risk of developing renal failure. Progress toward development of better DKD therapeutics is limited by an incomplete understanding of forces driving and connecting the various features of DKD, which include renal steatosis, fibrosis, and microvascular dysfunction. Herein we review the literature supporting roles for bioactive ceramides as inducers of local and systemic DKD pathology. In rodent models of DKD, renal ceramides are elevated, and genetic and pharmacological ceramide-lowering interventions improve kidney function and ameliorate DKD histopathology. In humans, circulating sphingolipid profiles distinguish human DKD patients from diabetic controls. These studies highlight the potential for ceramide to serve as a central and therapeutically tractable lipid mediator of DKD.

Extracellular vesicles metabolic changes reveals plasma signature in stage-dependent diabetic kidney disease

“…In the pathological process of DKD, increased activity of sphingomyelin choline synthase leads to the accumulation of sphingomyelin choline in podocytes, while inhibition of sphingomyelin choline conversion in animal studies can alleviate podocyte injury and reduce proteinuria [ 39 , 40 ]. Recent studies have proposed the pathological mechanism of ceramide-mediated kidney disease [ 41 ]. The two sphingolipids, S1P and Cer (d18:1/24:1(15Z)), identified in this study were highly correlated with DKD and, thus, may be useful as early biomarkers of DKD.…”

Renal Lipid Metabolism Abnormalities in Obesity and Clear Cell Renal Cell Carcinoma

“…The mechanisms linking lipid accumulation to cellular injury (lipotoxicity) and dysfunction in the kidney and other organs have been reviewed extensively [ 27 , 34 , 35 , 36 , 37 , 38 ]. Lipid accumulation per se is not thought to be deleterious to the cell (except in extreme cases) but serves as an indicator of disturbed lipid metabolism and as a dynamic reservoir of excess fatty acids.…”

“…Declining NAD + may also affect the function of NAD + -dependent enzymes that are essential for DNA repair, such as sirtuins and poly (ADP-ribose) polymerases (PARP) [ 132 ]. When FFA oversupply exceeds the cell’s beta-oxidative capacity, excess FFA is stored in lipid droplets (i.e., lipid accumulation), and may also enter alternative metabolic pathways, resulting in the formation of lipotoxic metabolites, such as ceramides and diacylglycerol [ 37 , 133 ]. Lipotoxicity, oxidative stress, and lipid peroxidation may lead to DNA damage, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction [ 134 , 135 , 136 , 137 ].…”

Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice

“…GLP-1RAs modulate kidney sodium homeostasis via NHE3 activity ( Carraro-Lacroix et al, 2009 ) and lower circulating RAS concentrations ( Skov, 2014 ), reducing oxidative stress ( Rodriguez et al, 2020 ) and decreasing ectopic lipid accumulation ( Wang et al, 2018 ; Guo et al, 2018 ). Among them, lipotoxicity in the progression of DKD has gained considerable attention in recent years ( Nicholson et al, 2020 ; Kim et al, 2021 ). Lipid droplets were found in the glomerular and tubular portion of DKD patients ( Thongnak et al, 2020 ).…”