Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease

Polycystic kidney disease (PKD) is a common genetic disease characterized by the proliferation of epithelial cells, formation of cysts, and the progression of renal deficiency. We have investigated a possible role of glycosphingolipids in the proliferation of human kidney cells in this disease. The levels of glucosylceramide and lactosylceramide and the activity of glucosylceramide synthase (GlcT-1) and lactosylceramide synthase (GAlT-2) were elevated 2-fold and 3-fold, respectively, in the PKD tissue compared to control. Lactosylceramide, but not glucosylceramide (10 μM) derived from PKD exerted a 4-fold stimulation in the proliferation of these cells. However, at a concentration of 40 μM, lactosylceramide and glucosylceramide both stimulated cell proliferation on the order of 10-fold and 2.5-fold, respectively, as compared to control. This phenomenon may be due to the enrichment of lactosylceramide containing shorter chain tarry acids (C16:0- C18:0). Lactosylceramide, but not glucosyl-ceramide exerted a time-dependent stimulation in the phosphorylation of mitogen-activated protein kinase (p⁴⁴ MAPK) in normal human kidney proximal tubular cells. Moreover, the kidneys and cultured cells from the PKD patients contained higher levels of the p⁴⁴ MAPK as compared to normal human kidneys. In sum, our studies indicate that lactosyl-ceramide present in the PKD kidney may stimulate cell proliteration via activation of the p⁴⁴ MAPK, and contribute to the pathophysiology in this disease.