Abstract

ORTIZ, Alberto  and  SANCHEZ-NINO, Maria Dolores. Glucosylceramides and kidney disease. Port J Nephrol Hypert [online]. 2017, vol.31, n.3, pp.200-206. ISSN 0872-0169.

Glucosylceramides are part of the wider family of glycosylceramides. Glucosylceramide synthase catalyzes the incorporation of a single glucose residue into ceramide to yield glucosylceramide. Glucosylceramide is known as a precursor for globotriaosylceramide (Gb3). In the cell membrane, Gb3 acts a receptor for verotoxin and plays a key role in allowing verotoxin entry into endothelial cells. Verotoxin causes endothelial cell injury leading to microangiopathy in hemolytic uremic syndrome. Additionally, Gb3 accumulates mainly in lysosomes in Fabry disease, caused by an X-linked deficiency in alfa-galactosidase A. Accumulated Gb3 is metabolized to lyso-Gb3, a circulating water soluble molecule that elicits a stress response in podocytes similar to the response elicited by high glucose levels. The activation of Notch 1, CD74 expression and autocrine secretion of TGF-β1 induced by lyso-Gb3 and high glucose levels may underlie the characteristic fibrosis observed in both diabetic nephropathy and Fabry nephropathy. While current therapy for Fabry disease consists mainly of enzyme replacement therapy, glucosylceramide synthase inhibitors, such as lucerastat and venglustat, are undergoing clinical trials as substrate reduction therapy, aiming at decreasing Gb3 synthesis. Additionally, eliglustat is already in clinical use to treat Gaucher disease. Preclinical evidence has shown an excess accumulation of glycosylceramides in acute kidney injury and polycystic kidney disease. Furthermore, glucosylceramide synthase inhibitors are protective in polycystic kidney disease, suggesting a wider role of glucosylceramide or derivatives in kidney injury. However, inhibition of glucosylceramide synthase increases the severity of preclinical acute kidney injury, probably through increase ceramide accumulation, although direct toxicity of a specific drug could not be ruled out. This adds a note of caution for clinical studies, at least for some glucosylceramide synthase inhibitors

Keywords : Fabry Disease; Lyso-Gb3; Diabetic Kidney Disease; Polycystic Kidney Disease; Acute Kidney Injury; Glucosylceramide; Glucosylceramide Synthase; Venglustat.

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