Dojuksan ameliorates tubulointerstitial fibrosis through irisin-mediated muscle-kidney crosstalk
Dojuksan ameliorates tubulointerstitial fibrosis through irisin-mediated muscle-kidney crosstalk
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DOI：
10.1016/j.phymed.2020.153393
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发表时间：
2021-01-01
期刊：
影响因子：
7.9
通讯作者：
Ha, Hunjoo
中科院分区：
文献类型：
--
作者：
Jiang, Songling;Oh, Dal-Seok;Ha, Hunjoo
背景：肌肉减少症在慢性肾脏病（CKD）中进展，并与终末期肾脏病患者的死亡率呈正相关。循环鸢尾素是一种运动诱发的肌因子，在 CKD 阶段进展过程中逐渐减少。鸢尾素抑制肾纤维化的进展，这是 CKD 的最终常见结果。我们对 C2C12 细胞的初步研究表明，Dojuksan（一种草药煎剂）可增加 PGC1 α（鸢尾素调节剂）和 FNDC5（鸢尾素前体）的表达。假设：Dojuksan 可能会增加循环鸢尾素并预防肾纤维化的进展。研究设计和方法：对七周大的雄性 C57BL/6 进行单侧输尿管梗阻 (UUO)诱导小鼠肾小管间质纤维化。 Dojuksan（50、100 或 200 mg/kg/天）或氯沙坦（1.5 mg/kg/天）是 CKD 的标准临床治疗方法，在手术前一天口服，并持续 7 天。为了确定肌肉释放的鸢尾素的作用，用来自经 Dojuksan 处理的转染 FNDC5 siRNA 的 C2C12 肌肉细胞的条件培养基 (CM) 处理 TGF β 刺激的小鼠近端肾小管上皮细胞（mProx24 细胞）。结果：UUO 小鼠表现出肌肉萎缩和进行性肾损伤。与氯沙坦类似，Dojuksan 可以改善 UUO 小鼠的肾脏炎症和纤维化。 Dojuksan（而非氯沙坦）增加了 UUO 小鼠的血浆鸢尾素浓度。 Dojuksan 显着增加 C2C12 细胞中基础 FNDC5 表达，并抑制 TNF α 诱导的和硫酸吲哚酚诱导的 FNDC5 下调。 Dojuksan 处理后，来自 C2C12 细胞的 CM 有效抑制了 mProx24 细胞中 TGF β 诱导的胶原蛋白 I (COL1) 上调。此外，鸢尾素可抑制 mProx24 细胞中 TGF β 诱导的 COL1，而转染 FNDC5 siRNA 的 C2C12 细胞的 CM 不会对其影响。结论：Dojuksan 通过鸢尾素介导的肌肉-肾脏串扰改善肾纤维化，表明 Dojuksan 可用作 CKD 的替代治疗剂。
Background: Sarcopenia progresses in chronic kidney disease (CKD) and is positively correlated with mortality in end-stage kidney disease patients. Circulating irisin, an exercise-induced myokine, gradually decreases during CKD stage progression. Irisin inhibits the progression of kidney fibrosis, which is the final common outcome of CKD. Our preliminary study with C2C12 cells showed that Dojuksan, a herbal decoction, increases the expression of PGC1 alpha (a regulator of irisin) and FNDC5 (a precursor of irisin).Hypothesis: Dojuksan may increase circulating irisin and prevent the progression of kidney fibrosis.Study Design and Methods: Unilateral ureteral obstruction (UUO) was performed on seven-week-old male C57BL/6 mice to induce kidney tubulointerstitial fibrosis. Dojuksan (50, 100, or 200 mg/kg/day) or losartan (1.5 mg/kg/day), a standard clinical treatment for CKD, was administered orally one day prior to surgery and continued for seven days thereafter. To determine the role of irisin released from muscles, TGF beta-stimulated murine proximal tubular epithelial cells (mProx24 cells) were treated with conditioned media (CM) from Dojuksan-treated C2C12 muscle cells transfected with FNDC5 siRNA.Results: UUO mice exhibited muscle wasting along with progressive kidney injury. Similar to losartan, Dojuksan ameliorated kidney inflammation and fibrosis in UUO mice. Dojuksan, but not losartan, increased plasma irisin concentration in UUO mice. Dojuksan significantly increased basal FNDC5 expression and inhibited TNF alpha-induced and indoxyl sulfate-induced FNDC5 down-regulation in C2C12 cells. The TGF beta-induced collagen I (COL1) up-regulation in mProx24 cells was effectively inhibited by CM from C2C12 cells after Dojuksan treatment. Moreover, irisin inhibited TGF beta-induced COL1 in mProx24 cells, which was not affected by CM from C2C12 cells transfected with FNDC5 siRNA.Conclusion: Dojuksan ameliorates kidney fibrosis through irisin-mediated muscle-kidney crosstalk, suggesting that Dojuksan may be used as an alternative therapeutic agent against CKD.