Diabetic nephropathy induces alterations in the glomerular and tubule lipid profiles

Abstract

Diabetic nephropathy (DN) is a major life-threatening complication of diabetes. Renal lesions affect glomeruli and tubules, but the pathogenesis is not completely understood. Phospholipids and glycolipids are molecules that carry out multiple cell functions in health and disease, and their role in DN pathogenesis is unknown. We employed high spatial resolution MALDI imaging MS to determine lipid changes in kidneys of eNOS−/−db/db mice, a robust model of DN. Phospholipid and glycolipid structures, localization patterns, and relative tissue levels were determined in individual renal glomeruli and tubules without disturbing tissue morphology. A significant increase in the levels of specific glomerular and tubular lipid species from four different classes, i.e., gangliosides, sulfoglycosphingolipids, lysophospholipids, and phosphatidylethanolamines, was detected in diabetic kidneys compared with nondiabetic controls. Inhibition of nonenzymatic oxidative and glycoxidative pathways attenuated the increase in lipid levels and ameliorated renal pathology, even though blood glucose levels remained unchanged. Our data demonstrate that the levels of specific phospho- and glycolipids in glomeruli and/or tubules are associated with diabetic renal pathology. We suggest that hyperglycemia-induced DN pathogenic mechanisms require intermediate oxidative steps that involve specific phospholipid and glycolipid species. Diabetic nephropathy (DN) is a major life-threatening complication of diabetes. Renal lesions affect glomeruli and tubules, but the pathogenesis is not completely understood. Phospholipids and glycolipids are molecules that carry out multiple cell functions in health and disease, and their role in DN pathogenesis is unknown. We employed high spatial resolution MALDI imaging MS to determine lipid changes in kidneys of eNOS−/−db/db mice, a robust model of DN. Phospholipid and glycolipid structures, localization patterns, and relative tissue levels were determined in individual renal glomeruli and tubules without disturbing tissue morphology. A significant increase in the levels of specific glomerular and tubular lipid species from four different classes, i.e., gangliosides, sulfoglycosphingolipids, lysophospholipids, and phosphatidylethanolamines, was detected in diabetic kidneys compared with nondiabetic controls. Inhibition of nonenzymatic oxidative and glycoxidative pathways attenuated the increase in lipid levels and ameliorated renal pathology, even though blood glucose levels remained unchanged. Our data demonstrate that the levels of specific phospho- and glycolipids in glomeruli and/or tubules are associated with diabetic renal pathology. We suggest that hyperglycemia-induced DN pathogenic mechanisms require intermediate oxidative steps that involve specific phospholipid and glycolipid species. The global epidemic of diabetes is a major health problem. Diabetic nephropathy (DN) can develop in about 1/3 of diabetic individuals and is characterized by specific glomerular and tubular lesions in the kidney. These lesions are associated with progression to end stage renal disease with subsequent requirement for renal dialysis and transplantation (1Collins A.J. Foley R.N. Chavers B. Gilbertson D. Herzog C. Johansen K. Kasiske B. Kutner N. Liu J. St. Peter W. et al.United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States.Am. J. Kidney Dis. 2012; 59: e1-e420Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Despite the significance of DN, there is still incomplete understanding of the pathogenic mechanisms, particularly those underlying the differential susceptibility to DN. Lipids may play a role in DN, but to date, the research focus has been on neutral lipids such as triacylglycerols and cholesterol (2Rutledge J.C. Ng K.F. Aung H.H. Wilson D.W. Role of triglyceride-rich lipoproteins in diabetic nephropathy.Nat. Rev. Nephrol. 2010; 6: