Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure1. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging2,3,4,5,6,7,8. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways1. Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes9. We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase–mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.
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We thank V. Gattone (Indiana University School of Medicine) for the kind gift of pcy breeding pairs and advice on colony maintenance. We thank S. Jones and the staff of Rodent Experimental Models (Worcester, Massachusetts) for production of the Pkd1 conditional knockout mice. We thank the staff of the Genzyme Departments of Comparative Medicine and Histology for help with in vivo studies and sample preparations. We thank S. Moreno for expert technical assistance. We are grateful to K. McEachern, R. Sacchiero, D. Copeland, S. Cheng, N. Yew, A. Smith, R. Gregory, T. Sybertz, K. Klinger and J. Burns for helpful discussions and comments on this manuscript.
T.A.N., L.A.S., K.A.R., B.W., S.K., Y.B., A.B., N.O.B., W.R.D., H.H., R.J.R., S.R.L., J.P.L. and O. I.-B. are all employed by Genzyme. J.A.S. holds intellectual property rights for Genzyme.
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Natoli, T., Smith, L., Rogers, K. et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med 16, 788–792 (2010). https://doi.org/10.1038/nm.2171
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