Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
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DOI：
10.1016/j.kint.2016.01.017
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发表时间：
2016-05
影响因子：
19.6
通讯作者：
Crowley SD
中科院分区：
文献类型：
--
作者：
Madan B;Patel MB;Zhang J;Bunte RM;Rudemiller NP;Griffiths R;Virshup DM;Crowley SD
活化的Wnt信号传导在肾纤维化的发病机制中至关重要，肾纤维化是大多数形式的慢性肾脏疾病的最终共同途径。已经提出了通过抑制单个Wnt或下游Wnt/β-连环蛋白信号传导的治疗性干预，但这些方法不中断所有Wnt的功能，也不阻断非经典Wnt信号传导途径。或者，口服生物可利用的小分子Wnt-C59阻断Wnt-酰基转移酶豪猪的催化活性，从而防止所有Wnt同种型的分泌。我们发现，抑制豪猪显着减弱小鼠单侧输尿管梗阻模型中的肾纤维化。Wnt-C59处理类似地钝化了阻塞肾中的胶原mRNA表达。与其广泛阻止Wnt信号传导的作用一致，豪猪抑制减少了Wnt靶基因的表达，并在输尿管梗阻后支持了肾中β-连环蛋白的核排斥。重要的是，Wnt-C59对Wnt分泌的阻止减弱了阻塞肾脏中炎性细胞因子的表达，否则这些炎性细胞因子会在产生胶原的成纤维细胞和上皮细胞中引起Wnt表达的正反馈回路。因此，豪猪的治疗靶向不仅通过克服个体Wnt同种型的冗余，而且通过防止上游精氨酸诱导的Wnt产生来消除肾纤维化。这些发现揭示了一种新的治疗策略，通过中断局部产生的炎性细胞因子和Wnt/β-连环蛋白信号通路之间的致病性串扰回路来保护肾脏免受纤维化。
Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.