Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Abstract

Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

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

“…1C). As we previously reported in lupus nephritis (41), GSLs in db/db mice were elevated at least in part in the glomeruli. We have recently reported that GSL levels in hematopoietic and leukemia cells are in part determined by glucose availability (47).…”

“…Levels of GSLs in the urine of diabetic patients were consistent with those observed for other kidney diseases in which GSLs play a role. For example, we recently reported elevated levels of GSLs in the urine of patients with lupus nephritis (41). In addition, levels and activity of the enzyme neuraminidase were also increased in the urine of lupus nephritis patients (41).…”

“…1, A and B). We have recently reported (41) increased GSL levels in the kidneys and urine of lupus-prone mice. Similarly, urinary hexosyl and LacCers were increased in db/db mice at 9 wk of age (Fig.…”

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

“…The literature indicates that inhibition of glucosylceramide synthesis dampens the inflammatory response (35,63), suggesting that inhibition of glucosylceramide synthesis in cisplatin-induced AKI could also reduce inflammatory pathways. Inflammatory pathways are known to perpetuate cisplatin-induced kidney injury; however, our data suggest that ceramide and/or a lack of its metabolism to a protective glycosphingolipid species play a role in the inflammatory response in cisplatininduced AKI.…”

“…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).…”