Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.
Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.
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DOI：
10.1038/s41598-022-13390-z
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发表时间：
2022-06-04
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
大量患有慢性肾病（CKD）的患者出现心脏肥大，这可能导致心力衰竭和心源性猝死。可溶性 klotho (sKL) 是跨膜蛋白 klotho 的脱落胞外域，可保护心脏免受肥厚性生长。我们已经证明，sKL 通过靶向神经节苷脂 GM1/GM3 的唾液酸部分来调节脂筏的形成和功能，从而保护心脏。循环 sKL 的减少会导致小鼠心脏肥大的风险增加。 sKL 替代疗法已被考虑，但其使用因无法大量生产该蛋白质而受到限制。因此，提出了保护心脏的替代方法。葡萄糖神经酰胺合酶催化的神经酰胺的糖基化是神经节苷脂形成的入口步骤。在这里，我们发现口服葡萄糖神经酰胺合酶抑制剂（GCSi）会减少血浆和心脏组织的鞘糖脂，包括神经节苷脂。 GCSi 的给药对两种心脏应激诱导的小鼠模型具有保护作用，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。 GCSi 治疗不会改变 CKD 肾功能不全和高血压的严重程度。这些结果为靶向葡萄糖神经酰胺合酶以减少神经节苷脂作为心脏肥大的治疗提供了原理证明。他们还支持 sKL 通过靶向神经节苷脂来保护心脏的假设。
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.
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影响因子：
3.7
作者：
Kitagawa M;Sugiyama H;Morinaga H;Inoue T;Takiue K;Ogawa A;Yamanari T;Kikumoto Y;Uchida HA;Kitamura S;Maeshima Y;Nakamura K;Ito H;Makino H
通讯作者：
Makino H
影响因子：
39.3
作者：
Andersson L;Cinato M;Mardani I;Miljanovic A;Arif M;Koh A;Lindbom M;Laudette M;Bollano E;Omerovic E;Klevstig M;Henricsson M;Fogelstrand P;Swärd K;Ekstrand M;Levin M;Wikström J;Doran S;Hyötyläinen T;Sinisalu L;Orešič M;Tivesten Å;Adiels M;Bergo MO;Proia R;Mardinoglu A;Jeppsson A;Borén J;Levin MC
通讯作者：
Levin MC
DOI：
10.1006/bbrc.2000.4226
发表时间：
2001-02-02
影响因子：
3.1
作者：
Koh, N;Fujimori, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
9.2
作者：
An, Sung-Wan;Cha, Seung-Kuy;Huang, Chou-Long
通讯作者：
Huang, Chou-Long
影响因子：
20.1
作者：
Makarewich CA;Zhang H;Davis J;Correll RN;Trappanese DM;Hoffman NE;Troupes CD;Berretta RM;Kubo H;Madesh M;Chen X;Gao E;Molkentin JD;Houser SR
通讯作者：
Houser SR