Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival.
Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival.
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DOI：
10.14814/phy2.12537
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发表时间：
2015-10
影响因子：
2.5
通讯作者：
Ho J
中科院分区：
文献类型：
--
作者：
Phua YL;Chu JY;Marrone AK;Bodnar AJ;Sims-Lucas S;Ho J
MicroRNAs是一种小的非编码RNA，它在转录后调节mRNA水平。虽然以前的研究已经证明miRNAs在肾单位祖细胞和输尿管芽血统中是不可或缺的，但对肾脏发育过程中的间质miRNAs了解很少。肾间质(以FoxD1表达为标志)形成肾间质、肾小管周毛细血管亚群和多种支持性血管细胞类型，包括周细胞和肾小球系膜细胞。在本研究中，我们获得了FoxD1GC；Dicerfl/fl转基因小鼠，这些小鼠在FoxD1系中缺乏miRNA的生物发生。DICER活性的丧失导致多方面的肾脏异常，包括肾脏发育受扰、肾母细胞扩张、肾素表达细胞减少、平滑肌传入小动脉减少，以及成熟肾小球的系膜细胞进行性丢失。尽管FoxD1+间质的最初谱系特征没有受到干扰，但肾小球系膜和肾间质都出现了异位凋亡，这与Bcl211(Bim)和P53效应基因(Bax、Trp53inp1、Jun、CDKN1A、MMP2和Arid3a)的表达增加有关。结合高通量的FoxD1+来源细胞的miRNA图谱和FoxD1GC；Dicerf1/f1肾脏中差异表达转录本的mRNA图谱，至少有72个miRNA：mRNA靶标相互作用被鉴定为抑制了凋亡程序。综上所述，这些结果支持间质miRNAs在肾脏发育过程中对细胞凋亡的调节中起着不可或缺的作用。
MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1GC;Dicerfl/fl transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1+ stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1+-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1GC;Dicerfl/fl kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.