Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease

A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.