Hyperglycemia and alteration in sphingolipids are early mediators of diabetic kidney disease: role of elongase 1 (Elovl1)

Abstract

Introduction Diabetic kidney disease (DKD) is characterized by impairment of renal glomerular and tubular cells. Low plasma levels of ceramides and lactosylceramides containing very long-chain (VLC) fatty acid were found to be predictive of DKD development. Elongase 1 (Elovl1) is a ubiquitous elongase that elongates C20-C22 fatty acids to generate very long-chain C24 fatty acids. Using a novel transgenic mouse overexpressing Elovl1, we investigated whether modification to sphingolipid fatty acid composition averts DKD development. Methods A transgenic (TG) mouse overexpressing Elovl1 was created at the Medical University of South Carolina/Transgenic Core. Elovl1 TG and wild type (WT) mice were rendered diabetic using serial streptozotocin injections. Plasma, kidney, liver, and urine sphingolipidomics of diabetic and non-diabetic TG and WT mice were analyzed using mass spectroscopy and Matrix-Assisted Laser Desorption/Ionization-Imaging Mass Spectrometry. Sphingolipid metabolizing enzymes were analyzed using immunohistochemical & multispectral imaging coupled with digital analysis. Results Plasma sphingomyelins were higher, but lactosylceramides were lower in diabetic TG than in diabetic WT mice. Kidney lactosylceramides were also lower in diabetic TG mice. In urine, diabetic TG mice excreted more VLC lactosylceramides than diabetic WT mice, but less VLC sphingomyelins, VLC ceramides, sphingosine and sphingosine 1-phosphate. There was extensive damage to proximal tubules in kidneys of diabetic WT mice compared to diabetic TG mice. Glomeruli in diabetic WT kidneys appeared also abnormal, whereas no obvious abnormality of glomeruli in diabetic TG was observed. In diabetic TG, Elovl1 overexpression resulted in decreased kidneys levels of both ceramide synthase and acid sphingomyelinase, but increased acid ceramidase levels compared to non-diabetic TG mice. Conclusion The diabetic Elovl1 TG mouse revealed interaction between Elovl1 overexpression and DKD development, and showed that distinct VLC sphingolipids could be involved in maintaining cell membrane integrity of renal cells.