Ceramides and Acute Kidney Injury

Abstract

Altered lipid metabolism is a characteristic feature and potential driving factor of acute kidney injury (AKI). Of the lipids that accumulate in injured renal tissues, ceramides are potent regulators of metabolism and cell fate. Up-regulation of ceramide synthesis is a common feature shared across several AKI etiologies in vitro and in vivo. Furthermore, ceramide accumulation is an early event in the natural history of AKI that precedes cell death and organ dysfunction. Emerging evidence suggests that inhibition of ceramide accumulation may improve renal outcomes in several models of AKI. This review examines the landscape of ceramide metabolism and regulation in the healthy and injured kidney. Furthermore, we discuss the body of literature regarding ceramides as therapeutic targets for AKI and consider potential mechanisms by which ceramides drive kidney pathogenesis.

Keywords: Acute kidney injury; ceramides; sphingolipids.

Figure 1.

Ceramide synthesis. Ceramides are produced via de novo biosynthesis, sphingomyelin hydrolysis, or salvage of sphingoid bases. The ubiquitous de novo pathway is characterized by the transfer of serine to palmitoyl CoA, producing a sphingoid backbone that subsequently is acylated and desaturated to form ceramide. Alternatively, cleavage of a choline headgroup by a family of sphingomyelinase enzymes rapidly converts sphingomyelin to ceramide. Lastly, re-acylation of liberated (dihydro)sphingosine by the (dihydro)ceramide synthase enzymes regenerates ceramides in the salvage pathway. The length of acyl chain incorporated into a ceramide molecule is dependent on the substrate specificity of the (dihydro)ceramide synthases. Abbreviations: CDase, ceramidase; CERS, (dihydro)ceramide synthase; DAG, diacylglycerol; DES, dihydroceramide desaturase; FFA, free fatty acid; SK, sphingosine kinase; PC, phosphatidylcholine; R, accessory acyl chain; SK, sphingosine kinase; SM, sphingomyelin; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPT, serine palmitoyltransferase; S1P, sphingosine 1-phosphate; 3KSR, 3-ketosphinganine reductase. Figure was created with BioRender.com.

Figure 2.

Expression of ceramide-related genes throughout the nephron. Ceramide-related gene expression throughout the nephron cell types and segments was quantified via single-nucleus RNA sequencing in healthy human kidneys (n = 13) and accessed via the Kidney Precision Medicine Project Kidney Tissue Atlas. Gene expression is characterized by the percentage of cells within each identified cluster expressing the target (dot size) and the average relative expression of the cell cluster (dot hue). Abbreviations: ATL, ascending thin limb cell; CCD-IC-A, cortical collecting duct intercalated cell type A; CCD-PC, cortical collecting duct principal cell; CNT, connecting tubule cell; CNT-IC-A, connecting tubule intercalated cell type A; CNT-PC, connecting tubule principal cell; C-TAL, cortical thick ascending limb cell; DCT1, distal convoluted tubule cell type 1; DCT2, distal convoluted tubule cell type 2; DTL1, descending thin limb cell type 1; DTL2, descending thin limb cell type 2; DTL3, descending thin limb cell type 3; IC-B, intercalated cell type B; IMCD, inner medullary collecting duct cell; MC, mesangial cell; MD, macula densa cell; M-TAL, medullary thick ascending limb cell; OMCD-IC-A; outer medullary collecting duct intercalated cell type A; OMCD-PC, outer medullary collecting duct principal cell; PapE, papillary tip epithelial cell; PEC, parietal epithelial cell; POD, podocyte; PT-S1, proximal tubule epithelial cell segment 1; PT-S2, proximal tubule epithelial cell segment 2; PT-S3, proximal tubule epithelial cell segment 3. Figure was created based on data generated by the Kidney Precision Medicine Project (KPMP): DK114886, DK114861, DK114866, DK114870, DK114908, DK114915, DK114926, DK114907, DK114920, DK114923, DK114933, and DK114937 (https://www.kpmp.org; data were downloaded on July 1, 2022).