Expression, Circulation, and Excretion Profile of MicroRNA-21, -155, and -18a Following Acute Kidney Injury

Toxicological Sciences, Oct 2012

MicroRNAs (miRNAs) are endogenous noncoding RNA molecules that are involved in post-transcriptional gene silencing. Using global miRNA expression profiling, we found miR-21, -155, and 18a to be highly upregulated in rat kidneys following tubular injury induced by ischemia/reperfusion (I/R) or gentamicin administration. Mir-21 and -155 also showed decreased expression patterns in blood and urinary supernatants in both models of kidney injury. Furthermore, urinary levels of miR-21 increased 1.2-fold in patients with clinical diagnosis of acute kidney injury (AKI) (n = 22) as compared with healthy volunteers (n = 25) (p < 0.05), and miR-155 decreased 1.5-fold in patients with AKI (p < 0.01). We identified 29 messenger RNA core targets of these 3 miRNAs using the context likelihood of relatedness algorithm and found these predicted gene targets to be highly enriched for genes associated with apoptosis or cell proliferation. Taken together, these results suggest that miRNA-21 and -155 could potentially serve as translational biomarkers for detection of AKI and may play a critical role in the pathogenesis of kidney injury and tissue repair process.

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Expression, Circulation, and Excretion Profile of MicroRNA-21, -155, and -18a Following Acute Kidney Injury

Janani Saikumar 2 3 Dana Hoffmann 2 3 Tae-Min Kim 0 2 Victoria Ramirez Gonzalez 1 2 3 Qin Zhang 2 5 Peter L. Goering 2 5 Ronald P. Brown 2 5 Vanesa Bijol 2 4 Peter J. Park 0 2 Sushrut S. Waikar 2 3 Vishal S. Vaidya 2 3 0 Center for Biomedical Informatics, Harvard Medical School , Boston, MA 1 Departamento de Nefrologia y Metabolismo Mineral, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran , Mexico 2 Hospital, Harvard Medical School and Department of Environmental Health, Harvard School of Public Health, Harvard Institutes of Medicine , Rm 562, 77 Avenue Louis Pasteur, Boston, MA 02115. Fax: (617) 525-5965 3 Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School , Boston, MA 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School , Boston, MA 5 Center for Devices and Radiological Health, Food and Drug Administration , Silver Spring, MD MicroRNAs (miRNAs) are endogenous noncoding RNA molecules that are involved in post-transcriptional gene silencing. Using global miRNA expression profiling, we found miR-21, -155, and 18a to be highly upregulated in rat kidneys following tubular injury induced by ischemia/reperfusion (I/R) or gentamicin administration. Mir-21 and -155 also showed decreased expression patterns in blood and urinary supernatants in both models of kidney injury. Furthermore, urinary levels of miR-21 increased 1.2-fold in patients with clinical diagnosis of acute kidney injury (AKI) (n=22) as compared with healthy volunteers (n=25) (p<0.05), and miR-155 decreased 1.5-fold in patients with AKI (p<0.01). We identified 29 messenger RNA core targets of these 3 miRNAs using the context likelihood of relatedness algorithm and found these predicted gene targets to be highly enriched for genes associated with apoptosis or cell proliferation. Taken together, these results suggest that miRNA-21 and -155 could potentially serve as translational biomarkers for detection of AKI and may play a critical role in the pathogenesis of kidney injury and tissue repair process. - Acute kidney injury (AKI) is a complex disease accompanied by a number of clinical conditions that is defined by loss of kidney function as illustrated by the glomerular filtration rate (Singbartl and Kellum, 2012). AKI has been shown to be a strong independent risk factor in developing progressive chronic kidney disease (CKD) and end-stage renal disease, in addition to other nonrenal outcomes, such as cardiovascular diseases (Bucaloiu et al., 2012; Coca et al., 2012; Lo et al., Disclaimer: The authors certify that all research involving human subjects was done under full compliance with all government policies and the Helsinki Declaration. 2009). Although considerable progress has been made in the management of AKI in both clinical and outpatient scenarios, the incidence of AKI among hospitalized adults increased from 61 to 288 per 100,000 population in the past decade (Waikar et al., 2006). AKI is associated consistently with higher risk and incidence of mortality even when taking into account comorbidities that may contribute to lung injury, liver injury, or other organ system failure (Chertow et al., 2005). The primary causes of AKI are thought to be ischemic and toxic insults that compromise the glomerular and tubular function (Thadhani etal.,1996). MicroRNAs (miRNAs) are endogenous short noncoding RNA molecules of about 22 nucleotides in length and are involved in post-transcriptional gene regulation by targeting messenger RNAs (mRNAs) and inhibiting translation (Bartel, 2004). MiRNAs are associated with numerous functional roles in development and disease pathogenesis in multiple organ systems (Ambros, 2004; Erson and Petty, 2008; Stefani and Slack, 2008). The hallmark of gene regulation by these small molecules is that a given miRNA may regulate multiple target mRNAs because of the imprecise complementarity in base pairing and, conversely, a single gene may be governed by several regulatory miRNAs (Bartel and Chen, 2004). Lower complexity, no post processing modification, synthetic high-affinity capture reagent, tissue-specific expression, and amplifiable signals make circulating/soluble small RNAs ideal candidates as biomarkers to reflect various pathophysiological conditions and disease states (Chen etal., 2008; Hede, 2009; Rabinowits etal., 2009; Rosell etal., 2009; Sharma and Vogel, 2009; Wang etal., 2009). Exosomal and circulating miRNAs have recently shown great potential as biomarkers for detecting cancers such as prostate cancer (Mitchell etal., 2008), colorectal cancer (Ng etal., 2009), ovarian cancer (Resnick etal., 2009), and nonsmall cell lung cancer (Chen etal., 2008; Rabinowits etal., 2009), in addition to myocardial injury (Ji etal., 2009)and liver damage (Laterza etal., 2009; Wang etal., 2009; Yang etal., 2012). Apart from their diagnostic application, the potential therapeutic applications of miRNAs are also currently of interest be (...truncated)


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Janani Saikumar, Dana Hoffmann, Tae-Min Kim, Victoria Ramirez Gonzalez, Qin Zhang, Peter L. Goering, Ronald P. Brown, Vanesa Bijol, Peter J. Park, Sushrut S. Waikar, Vishal S. Vaidya. Expression, Circulation, and Excretion Profile of MicroRNA-21, -155, and -18a Following Acute Kidney Injury, Toxicological Sciences, 2012, pp. 256-267, 129/2, DOI: 10.1093/toxsci/kfs210