Renal stromal miRNAs are required for normal nephrogenesis and glomerular mesangial survival

Physiological Reports

Yu Leng Phua¹  Jessica Y. S. Chu¹  April K. Marrone¹  Andrew J. Bodnar¹  Sunder Sims-Lucas¹ 

[1] Rangos Research Center, School of Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania

关键词: Glomerular mesangium;    kidney development;    microRNAs;    renal stroma;   

DOI  :  10.14814/phy2.12537

来源: Wiley

【 摘 要 】

Abstract

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 FoxD1^GC;Dicer^fl/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 FoxD1^GC;Dicer^fl/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.

【 授权许可】

CC BY   
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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