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Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells.

Title: Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells.
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Name(s): Subathra, Marimuthu, author
Korrapati, Midhun, author
Howell, Lauren A, author
Arthur, John M, author
Shayman, James A, author
Schnellmann, Rick G, author
Siskind, Leah J, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2015-08-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Glycosphingolipids (GSLs) play a role in insulin resistance and diabetes, but their role in diabetic nephropathy (DN) has received limited attention. We used 9- and 17-wk-old nondiabetic db/m and diabetic db/db mice to examine the role of GSLs in DN. Cerebrosides or monoglycosylated GSLs [hexosylceramides (HexCers); glucosyl- and galactosylceramides] and lactosylceramide (LacCers) were elevated in db/db mouse kidney cortices, specifically in glomeruli, and also in urine. In our recent paper (25), we observed that the kidneys exhibited glomerular hypertrophy and proximal tubular vacuolization and increased fibrosis markers at these time points. Mesangial cells contribute to hyperglycemia-induced glomerular hypertrophy in DN. Hyperglycemic culture conditions, similar to that present in diabetes, were sufficient to elevate mesangial cell HexCers and increase markers of fibrosis, extracellular matrix proteins, and cellular hypertrophy. Inhibition of glucosylceramide synthase or lowering glucose levels decreased markers of fibrosis and extracellular matrix proteins and reversed mesangial cell hypertrophy. Hyperglycemia increased phosphorylated (p)SMAD3 and pAkt levels and reduced phosphatase and tensin homolog levels, which were reversed with glucosylceramide synthase inhibition. These data suggest that inhibition of glucosylceramide synthase reversed mesangial cell hypertrophy through decreased pAkt and pSmad3 and increased pathways responsible for protein degradation. Importantly, urinary GSL levels were higher in patients with DN compared with healthy control subjects, implicating a role for these lipids in human DN. Thus, hyperglycemia in type II diabetes leads to renal dysfunction at least in part by inducing accumulation of HexCers and LacCers in mesangial cells, resulting in fibrosis, extracellular matrix production, and hypertrophy.
Identifier: FSU_pmch_26041445 (IID), 10.1152/ajprenal.00150.2015 (DOI), PMC4525094 (PMCID), 26041445 (RID), 26041445 (EID), ajprenal.00150.2015 (PII)
Keywords: Diabetic nephropathy, Glycosphingolipids, Hypertrophy, Kidney, Mesangial cells
Grant Number: P20-RR-17677, R01 GM084147, R01-GM-084147, R01-DK-101034, P30 CA138313, R01 DK093462, R01-DK-093462, P30-CA-138313, P20 RR017677
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525094.
Subject(s): Animals
Antigens, CD/metabolism
Cell Line
Cell Proliferation
Diabetes Mellitus, Experimental/pathology
Diabetic Nephropathies/metabolism
Diabetic Nephropathies/pathology
Glycosphingolipids/metabolism
Humans
Kidney/metabolism
Kidney Glomerulus/pathology
Kidney Tubules, Proximal/pathology
Lactosylceramides/metabolism
Mesangial Cells/pathology
Mesangial Cells/ultrastructure
Mice
Oncogene Protein v-akt/metabolism
Signal Transduction
Smad3 Protein/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26041445
Owner Institution: FSU
Is Part Of: American journal of physiology. Renal physiology.
1522-1466
Issue: iss. 3, vol. 309

Choose the citation style.
Subathra, M., Korrapati, M., Howell, L. A., Arthur, J. M., Shayman, J. A., Schnellmann, R. G., & Siskind, L. J. (2015). Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells. American Journal Of Physiology. Renal Physiology. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26041445