Therapeutic Potential of Progranulin in Hyperhomocysteinemia-Induced Cardiorenal Dysfunction
Therapeutic Potential of Progranulin in Hyperhomocysteinemia-Induced Cardiorenal Dysfunction
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颗粒体蛋白前体对高同型半胱氨酸血症引起的心肾功能障碍的治疗潜力
DOI：
10.1161/hypertensionaha.116.08154
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发表时间：
2017-02-01
期刊：
影响因子：
8.3
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Fu, Yi;Sun, Yu;Yi, Fan
高同型半胱氨酸血症（Hyperhomocysteinemia，hHcys）是心血管疾病和终末期肾病的重要独立危险因素。虽然在实验研究和临床试验中已经使用了多种降低同型半胱氨酸水平的方法，但没有有效的治疗方法可以完全预防同型半胱氨酸诱导的损伤。因此，确定致病途径中的关键分子可能提供线索，以开发新的治疗策略，用于治疗hHcys相关的损伤，而不是降低血浆同型半胱氨酸水平。在这项研究中，我们发现，自分泌生长因子颗粒蛋白前体（PGRN）的水平显着降低，在肾脏和心脏从小鼠模型的hHcys。我们进一步观察到，在hHcys中，PGRN缺陷型小鼠显著加重心肾损伤，如与野生型小鼠相比，更高水平的尿白蛋白排泄、更严重的肾形态学损伤（包括明显的肾小球基底膜增厚和足细胞足突消失）和不利的心肌重塑所证明的。从机制上讲，我们发现PGRN介导的Wnt/β-catenin信号转导是将同型半胱氨酸与心肾损伤联系起来的关键信号转导途径之一。重要的是，我们最终提供了直接的证据，PGRN的治疗潜力的小鼠与hHcys的预处理与重组人PGRN。总的来说，我们的研究结果表明，PGRN可能是一种创新的治疗策略，用于治疗hHcys患者。
Hyperhomocysteinemia (hHcys) is an important independent risk factor for the development of cardiovascular disease and end-stage renal disease. Although multiple approaches lowering the levels of homocysteine have been used in experimental studies and clinical trials, there is no effective therapy available to fully prevent homocysteine-induced injury. Therefore, identifying key molecules in the pathogenic pathways may provide clues to develop new therapeutic strategies for the treatment of hHcys-associated injury beyond lowering the plasma homocysteine levels. In this study, we found that the levels of progranulin (PGRN), an autocrine growth factor, were significantly reduced in the kidney and heart from a mouse model of hHcys. We further observed that in hHcys, PGRN-deficient mice significantly exacerbated cardiorenal injury as evidenced by higher levels of urinary albumin excretion, more severe renal morphological injuries, including pronounced glomerular basement membrane thickening and podocyte foot process effacement, and adverse myocardial remodeling versus wild-type mice. Mechanistically, we found that PGRN-medicated Wnt/&bgr;-catenin signaling was one of the critical signal transduction pathways that links homocysteine to cardiorenal injury. Importantly, we finally provided direct evidence for the therapeutic potential of PGRN in mice with hHcys by pretreatment with recombinant human PGRN. Collectively, our results suggest that PGRN may be an innovative therapeutic strategy for treating patients with hHcys.