Yang Ke, Wang Cheng, Nie Ling, Zhao Xiaohui, Gu Jun, Guan Xu, Wang Song, Xiao Tangli, Xu Xinli, He Ting, Xia Xuefeng, Wang Junping, Zhao Jinghong
Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of People's Liberation Army, Xinqiao Hospital.
Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, and.
J Am Soc Nephrol. 2015 Oct;26(10):2434-46. doi: 10.1681/ASN.2014060543. Epub 2015 Mar 24.
Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=-0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.
左心室肥厚（LVH）是慢性肾脏病（CKD）患者常见的并发症，也是死亡的独立危险因素。据报道，尿毒症溶质或Klotho水平的变化与CKD有关，而这些因素与CKD相关的LVH之间的关系仍不清楚。在此，我们研究了Klotho与典型尿毒症溶质硫酸吲哚酚（IS）在CKD相关LVH中的相互作用。在对86例CKD患者的调查中，发现血清IS水平与Klotho之间呈负相关（r = -0.59，P < 0.001）。此外，血清IS和Klotho水平与LVH独立相关（对于IS：r = 0.69，P < 0.001；对于Klotho：r = -0.49，P < 0.001）。在正常小鼠中，腹腔注射IS 8周可诱导LVH，同时伴有肾脏Klotho的显著下调。值得注意的是，IS诱导的LVH在杂合子Klotho缺陷（kl/+）小鼠中更严重。在体外，Klotho处理通过阻断氧化应激并抑制p38和细胞外信号调节蛋白激酶1/2信号通路，强烈抑制IS诱导的心肌细胞肥大。在CKD相关LVH的小鼠模型中，肾脏Klotho的表达低于健康对照组，血清IS水平高于健康对照组。此外，用Klotho蛋白治疗CKD小鼠可显著抑制LVH的发展。综上所述，这些结果表明Klotho是IS诱导的LVH的内源性保护因子，Klotho与IS之间的失衡可能导致CKD中LVH的发展。
