In Translation MicroRNAs in Kidney Disease: An Emerging Understanding Heba W.Z. Khella, MD, MSc, 1,2 Marize Bakhet, BSc, 1 Zsuzsanna Lichner, PhD, 1,3 Alexander D. Romaschin, PhD, DCC, FCACB, 1,3 Michael A.S. Jewett, MD, FRCSC, FACS, 2,4 and George M. Yousef, MD, PhD, FRCPC 1,2,3 MicroRNAs (miRNAs) are short noncoding RNA molecules that function by negatively regulating the expression of their target genes in a tightly controlled manner. Accumulating evidence, based in part on effects seen after miRNA overexpression and/or knockdown, points to the critical involvement of miRNAs in kidney function in health and disease. In this review, we provide a quick overview of the biogenesis of miRNAs and their potential involvement in kidney development and normal function. We also discuss the current literature that has begun to uncover the role of miRNAs in the pathogenesis of kidney diseases, including diabetic nephropathy, hypertension, glomerulonephritis, and cancer. As such, miRNAs have potential utility in the clinical realm as disease biomarkers. Moreover, miRNAs represent an attractive therapeutic target for a number of kidney diseases. We close by discussing a number of potential challenges that face the field of miRNA research and clinical use. Am J Kidney Dis. 61(5):798-808. Crown Copyright © 2013 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. INDEX WORDS: Kidney disease; microRNA; renal cell carcinoma; kidney development; kidney function; tumor markers; polycystic kidney disease; diabetes; hypertension. BACKGROUND M icroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by bind- ing to the 3= untranslated region (UTR) of their target messenger RNAs (mRNAs), resulting in translational repression and/or mRNA degradation. More than 1,527 miRNAs have been identified in humans to date, 1 and in recent years, miRNAs have been shown to be involved in a variety of biological processes, includ- ing development, cell differentiation, proliferation, and apoptosis. 2,3 In the past couple of years, evidence has emerged suggesting that miRNAs are key players in kidney development and are essential for normal function of the kidney. 4,5 Thus, it is not surprising that miRNA dysregulation has been observed in kidney diseases ranging from diabetes to hypertension and cancer. CASE VIGNETTE A 65-year-old woman was evaluated by abdominal ultrasound as part of an investigation of intermittent right upper-quadrant pain. As a young woman, she had undergone a left nephroureterec- tomy for chronic hydronephrosis and recurrent pyelonephritis secondary to reflux. Her estimated glomerular filtration rate was normal. The ultrasound revealed an incidental solid mass in a large but otherwise unremarkable right kidney. A computed tomographic scan confirmed the presence of a centrally located enhancing 4.5-cm renal mass consistent with renal cell carcinoma (RCC). She was referred for a kidney biopsy, but due to the location of the mass, the radiologist was unable to obtain diagnostic tissue of the lesion. The patient was advised to undergo resection, with the understanding that a nephrectomy might be required. During the procedure, the central mass was noted to be well demarcated from normal tissue, and a partial nephrectomy was performed and the pathology report revealed oncocytoma. There was some bleeding postoperatively, and her convalescence was complicated by a transient urinary fistula and acute kidney injury requiring temporary dialysis. She was discharged at 2 weeks. PATHOGENESIS miRNA Biogenesis As reviewed in more detail elsewhere, 6-8 the biogen- esis of miRNAs starts with the transcription of a primary miRNA (pri-miRNA) by RNA polymerase II or RNA polymerase III. 6-10 This step is regulated by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor  (TGF) (Fig 1). 11 Pri-miRNAs are long transcripts of several thousand nucleotides containing hairpin structures From the 1 Department of Laboratory Medicine and the Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital; 2 Institute of Medical Science and 3 Depart- ment of Laboratory Medicine and Pathobiology, University of Toronto; and 4 Division of Urologic Oncology, Princess Margaret Hospital, University Health Network, Department of Surgery, University of Toronto, Toronto, Canada. Received March 30, 2012. Accepted in revised form September 2, 2012. Originally published online December 7, 2012. Address correspondence to George M. Yousef, MD, PhD, FRCPC, Department of Laboratory Medicine, St. Michael’s, 30 Bond St, Toronto, ON, M5B 1W8, Canada. E-mail: yousefg@ smh.ca Crown Copyright © 2013 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. All rights reserved. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2012.09.018 Am J Kidney Dis. 2013;61(5):798-808 798