Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3
Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3
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DOI：
10.1152/ajprenal.00402.2018
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发表时间：
2018-12-01
影响因子：
4.2
通讯作者：
Bong, Zheng
中科院分区：
文献类型：
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作者：
Ma, Zhengwei;Wei, Qingqing;Bong, Zheng
肾纤维化是慢性肾脏病（CKD）的常见病理特征，包括糖尿病肾病（DKD）和阻塞性肾病。尽管 microRNA 在 CKD 肾小管损伤和肾纤维化中的总体作用尚不清楚，但多种 microRNA 与 DKD 和梗阻性肾病的发病机制有关。 Dicer（一种 microRNA 生物合成的关键 RNase III 酶）通过 Cre-lox 系统从小鼠肾近端小管中被特异性消除，以消耗 microRNA。近端肾小管 Dicer 敲除 (PT-Dicer KO) 小鼠和野生型 (WT) 同窝小鼠接受链脲佐菌素 (STZ) 治疗以诱导 DKD 或单侧输尿管梗阻 (UUO) 以诱导梗阻性肾病。检查肾肥大、肾小管凋亡、肾脏炎症和肾小管间质纤维化。与WT小鼠相比，PT-Dicer KO小鼠在STZ治疗后表现出更严重的肾小管损伤和肾脏炎症。这些小鼠还出现了更高水平的肾小管间质纤维化。同时，在对照和 STZ 处理的小鼠中，PT-Dicer KO 小鼠肾脏中的 Smad2/3 表达显着高于 WT 小鼠（6 个月龄）。同样，UUO 在 PT-Dicer KO 小鼠中诱导比 WT 更严重的肾损伤、炎症和间质纤维化。尽管我们没有在假手术小鼠（2-3 个月大）中检测到明显的 Smad2/3 表达，但在受阻的 PT-Dicer KO 肾脏中明显诱导了更多的 Smad2/3。这些结果支持 Dicer 依赖性 microRNA 合成在 CKD 肾损伤和纤维化发展中的保护作用，特别是在 DKD 和阻塞性肾病中。 Dicer 和 microRNA 的消耗可能上调 Smad2/3 相关信号通路，从而促进 CKD 的进展。
Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT-Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT-Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstinal fibrosis. Meanwhile, PT-Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT-Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2-3 mo old), significantly more Smad2/3 was induced in obstructed PT-Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.