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.