Combined Blockade of Smad3 and JNK Pathways Ameliorates Progressive Fibrosis in Folic Acid Nephropathy
Combined Blockade of Smad3 and JNK Pathways Ameliorates Progressive Fibrosis in Folic Acid Nephropathy
复制标题
联合阻断 Smad3 和 JNK 通路可改善叶酸肾病的进行性纤维化
DOI：
10.3389/fphar.2019.00880
复制
发表时间：
2019-08-09
影响因子：
5.6
通讯作者：
Yu, Xueqing
中科院分区：
文献类型：
--
作者：
Jiang, Mengjie;Fan, Jinjin;Yu, Xueqing
急性肾损伤通过肾小管间质纤维化导致慢性肾病是肾病的主要挑战。几种信号通路促进间质纤维化;然而，有效抑制纤维化可能需要阻断一种以上的通路。本研究调查了Smad 3和c-Jun N-末端激酶（JNK）信号传导的阻断是否增加了叶酸肾病间质纤维化的抑制作用。单次高剂量叶酸（FA）可导致C57 BL/6 J小鼠急性肾小管损伤，随后出现间质纤维化和慢性肾功能损害。Smad 3和JNK信号传导的共激活发生在小鼠FA诱导的肾病和人伊加肾病的肾小管间质损伤和纤维化区域的肾小管上皮细胞和肌成纤维细胞中。从FA给药后第6天开始，用Smad 3抑制剂（SIS 3）、JNK抑制剂（SP 600125）或其组合治疗各组小鼠，直至第28天处死。每种药物都有效地抑制其特异性靶点（Smad 3磷酸化或c-Jun磷酸化），而不影响其他途径。单独给药，每种药物部分减少肾纤维化，而联合治疗提供了一个附加的和深刻的保护肾纤维化和改善肾功能。在FA诱导的肾纤维化和炎症过程中，抑制Smad 3和/或JNK信号传导活性可防止肾小管上皮细胞中PGC-1α的下调和肌成纤维细胞中PGC-1α的上调。PGC-1α在Smad 3 −/− NRK 52 E细胞中表达上调，而在Smad 3 −/− NRK 49 F细胞中表达下调，表明Smad 3信号可能以不同的方式调节PGC-1α在肾小管上皮细胞和成纤维细胞中的表达。体内和细胞培养研究也表明，Smad 3和JNK信号通过直接作用于PGC-1α的转录，共同导致肾小管上皮细胞线粒体功能障碍和细胞损伤。这些途径还协同作用以时空方式促进肾成纤维细胞增殖。总之，我们已经确定了一种潜在的联合治疗进行性肾纤维化，其部分通过改变线粒体功能来起作用。
Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signaling pathways promote interstitial fibrosis; however, effective suppression of fibrosis may require blockade of more than one pathway. This study investigated whether blockade of Smad3 and c-Jun N-terminal kinase (JNK) signaling gives added suppression of interstitial fibrosis in folic acid nephropathy. A single high dose of folic acid (FA) causes acute tubular damage in C57BL/6J mice followed by interstitial fibrosis and chronic renal impairment. Co-activations of Smad3 and JNK signaling occur in both tubular epithelial cells and myofibroblasts in areas of tubulointerstitial damage and fibrosis in both murine FA-induced nephropathy and human IgA nephropathy. Groups of mice were treated with a Smad3 inhibitor (SIS3), a JNK inhibitor (SP600125), or a combination from day 6 after FA administration until being killed on day 28. Each drug efficiently inhibited its specific target (Smad3 phosphorylation or c–Jun phosphorylation) without affecting the other pathway. Given alone, each drug partially reduced renal fibrosis, whereas the combination therapy gave an additive and profound protection from renal fibrosis and improved renal function. Inhibition of Smad3 and/or JNK signaling activities prevented down-regulation of PGC-1α in tubular epithelial cells and up-regulation of PGC-1α in myofibroblasts during FA-induced renal fibrosis and inflammation. The expression of PGC-1α was upregulated in Smad3 −/− NRK52E cells while downregulated in Smad3 −/−NRK49F cells, suggesting that Smad3 signaling may regulate expression of PGC-1α in renal tubular epithelial cells and fibroblasts in distinct fashion. In vivo and cell culture studies also indicate that Smad3 and JNK signaling cooperate to cause mitochondrial dysfunction and cell damage in tubular epithelial cells via direct actions on the transcription of PGC-1α. These pathways also act cooperatively to promote renal fibroblast proliferation in tempo-spatial fashion. In conclusion, we have identified a potential combination therapy for progressive renal fibrosis which operates, in part, through modifying mitochondrial function.