Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, E300 GH, Iowa City, IA, 52242-1081, USA.
US Early Development, Synthetics Platform, Global CMC Development, Sanofi, Waltham, MA, 02451, USA.
Sci Rep. 2022 Jun 4;12(1):9340. doi: 10.1038/s41598-022-13390-z.
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.
大量患有慢性肾脏病 (CKD) 的患者会出现心肌肥大，这可能导致心力衰竭和心源性猝死。可溶性 klotho（klotho 的跨膜蛋白脱落的胞外域）可保护心脏免受肥大生长的影响。我们已经表明，sKL 通过靶向神经节苷脂的唾液酸部分 GM1/GM3，调节脂筏的形成和功能来保护心脏。循环中 sKL 的减少会增加小鼠发生心肌肥大的风险。已经考虑过 sKL 替代疗法，但由于无法大量生产这种蛋白质，其应用受到限制。因此，提出了保护心脏的替代方法。神经酰胺葡萄糖基转移酶催化的神经酰胺糖化是神经节苷脂形成的入口步骤。在这里，我们表明，口服神经酰胺葡萄糖基转移酶抑制剂 (GCSi) 可降低血浆和心脏组织糖脂，包括神经节苷脂。GCSi 的给药在两种心脏应激诱导的小鼠模型中具有保护作用，一种是异丙肾上腺素过度刺激，另一种是 5/6 肾切除术诱导的 CKD。在 CKD 中，用 GCSi 治疗不会改变肾功能不全和高血压的严重程度。这些结果为靶向葡萄糖基转移酶以减少神经节苷脂作为治疗心肌肥大的方法提供了原理证明。它们还支持 sKL 通过靶向神经节苷脂来保护心脏的假说。
