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

Abstract

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.

Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry

“…[49] In our conditions, treatment with BFA initiated the synthesis of HexCer at an earlier time point (8.6 min) while the maximal rate of synthesis remained unchanged reflecting the fact that the substrate availability for GCS is a function of trafficking of the label from the ER to the Golgi and not of the Cer availability. On the other hand, it has been shown that the formation of glycosphingolipids could be driven under high glucose conditions, thus pointing to UDPGlucose as the rate limiting factor in this metabolic step [50]. Interestingly, these results highlight a substantial difference between GCS and SMS utilization of Cer substrate transferred from the ER.…”

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

“…Thus, it is unclear whether it is the ceramides and/or the flux of ceramides into glycosphingolipids that are contributing to cisplatin-induced AKI. To elucidate the role of the ceramides and/or their metabolism to hexosylceramides independently of one another in cisplatin-induced AKI, we blocked metabolism of ceramides to glucosylceramides with a potent inhibitor of glucosylceramide synthase, named C10 (36). C10 is the 10-carbon analog of the Food and Drug Administrationapproved glucosylceramide synthase inhibitor, eliglustat.…”

“…Glucosylceramide, has been implicated to play a role in a variety of kidney diseases, such as diabetic nephropathy, lupus nephritis, and polycystic kidney disease, as well as decreased kidney function associated with aging (35)(36)(37)(38). Glucosylceramides have been implicated in regulating pathways involved in the above kidney diseases, including cell death, ER stress, and inflammation (23,39,40).…”

New insights into the effects of onion consumption on lipid mediators using a diet-induced model of hypercholesterolemia

“…Likewise, alterations in other sphingolipids as the level of glycosylceramides (such as HexCer and LacCer) have been noted in cells and tissues in response to cardiovascular disease, diabetes, skin disorders, cancer and renal dysfunction [56], [57]. However, recent studies have also reported certain inconsistency in the changes produced in glycosylated forms between different tissues and plasma.…”