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.

Keywords: ceramide; diabetic kidney disease; diabetic nephropathy; lipid metabolism; lipotoxicity; sphingolipids.

Figure 1

Histopathology of diabetic kidney disease. DKD elicits structural and functional changes to the glomerulus, tubules, and microvasculature of the kidney. ECM, extracellular matrix. Created with BioRender.com.

Figure 2

Proposed mechanisms of local ceramides in DKD pathology. (A) Schematic of sphingolipid metabolism. (B) Ceramides promote lipid accumulation via i) upregulation of CD36 and Srebf1 expression, ii) stimulation of CD36 translocation and SREBP-1 cleavage, and iii) inhibition of intracellular lipase expression. Ceramide and its targets PP2A and PKCζ inhibit Akt activation, impeding downstream cell survival (most cell types) or eNOS-dependent NO production (in endothelial cells). Ceramide antagonizes mitochondrial function by inhibiting ETC complex activity and permeabilizing mitochondrial membranes, leading to programmed cell death. Lastly, ceramide contributes to TGF-β signaling and tissue fibrosis, which may be partially mediated by SREBP-1. C1P, ceramide-1-phosphate; S1P, sphingosine-1-phosphate; FA, fatty acid; NO, nitric oxide; ETC, electron transport chain; MOMP, mitochondrial outer membrane permeabilization. Created with BioRender.com.