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)