Delineating the role of ceramides in kidney disease and fibrosis

作者：Mohammad Sako, Rebekah Nicholson, Divya Sundar, Lukas Kennett, Deborah Stuart, Alan Maschek, Will Holland, S A Summers, Nirupama Ramkumar · 发表于：Physiology · 年份：2026 · DOI：10.1152/physiol.2026.41.s1.2295027 · 研究领域：Sphingolipid Metabolism and Signaling、Biomedical Research and Pathophysiology、Chemotherapy-induced organ toxicity mitigation

Background: Ceramides are bioactive lipid species that contribute to lipotoxicity and cell death. The rate limiting, first step in the ceramide biosynthesis pathway is catalyzed by serine palmitoyl transferase (SPT) comprising of 3 different subunits (SPTLC1, SPTLC2, SPTLC3). In this study, we examined whether kidney tubule specific SPT overexpression was sufficient to induce tubular injury in C57BL/6 mice. Methods: We generated a transgenic mouse with overexpression of a fused construct encoding a functional SPT heterodimer fSPT(SPTLC1, SPTLC2 and ssSPTa) selectively in the kidney tubules by crossing floxed fSPT mice with mice carrying the Pax8-rtTA/LC1 transgenes. Male and female floxed fSPT mice and fSPTOE mice were treated with doxycycline chow (600mg/kg) for 14 days at 8 weeks of age. Metabolic balance studies were performed at 10 and 20 weeks of age for urine collection. Kidneys were isolated to evaluate kidney injury and histology. Overexpression of kidney ceramides was confirmed with lipidomic analyses. Statistical analyses were performed using unpaired Student’s t-test. Results: Compared to floxed controls, fSPTOE mice had a 5.3-fold increase in Sptlc1 and Sptlc2 expression in the kidneys (p< 0.01, n=8-10 mice/group for males, n=2-4 mice for females). Lipidomic analyses of kidneys demonstrated that fSPTOE mice had 1.68 fold higher ceramides (Cer 18:1;O2/22:0: 53,664 ± 15319 vs floxed: 30,779 ± 8763 pmol/g, p< 0.001), 6.54 fold higher dihydroceramides (Cer 18:0;...