MicroRNAs in acute kidney injury
Fan et al. Human Genomics
MicroRNAs in acute kidney injury
Pei-Chun Fan 3 4
Chia-Chun Chen 2
Yung-Chang Chen 4
Yu-Sun Chang 2
Pao-Hsien Chu 0 1 5 6
0 Healthcare Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University , Taipei , Taiwan
1 Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University , Taipei , Taiwan
2 Molecular Medicine Research Center, Chang Gung University , Taoyuan , Taiwan
3 Graduate Institute of Clinical Medical Sciences, Chang Gung University , Taoyuan , Taiwan
4 Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Medical Center , Taoyuan , Taiwan
5 Department of Cardiology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University , 199 Tung Hwa North Road, Taipei 105 , Taiwan
6 Heart Failure Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University , Taipei , Taiwan
Acute kidney injury (AKI) is an important clinical issue that is associated with significant morbidity and mortality. Despite research advances over the past decades, the complex pathophysiology of AKI is not fully understood. The regulatory mechanisms underlying post-AKI repair and fibrosis have not been clarified either. Furthermore, there is no definitively effective treatment for AKI. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs of 19~23 nucleotides that have been shown to be crucial to the post-transcriptional regulation of various cellular biological functions, including proliferation, differentiation, metabolism, and apoptosis. In addition to being fundamental to normal development and physiology, miRNAs also play important roles in various human diseases. In AKI, some miRNAs appear to act pathogenically by promoting inflammation, apoptosis, and fibrosis, while others may act protectively by exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenic effects. Thus, miRNAs have not only emerged as novel biomarkers for AKI; they also hold promise to be potential therapeutic targets. Abbreviations: AA, aristolochic acid; ADIPOR2, adiponectin receptor 2; AGO, argonaute; AKI, acute kidney injury; ATF3, activating transcription factor 3; B, blood; BCL-2, B cell lymphoma 2; BUMPT-306 cell, Boston University mouse proximal tubule cell clone 306; CdCl2, cadmium chloride; CRL-2753 cell, rat mesangial cell line; CKD, chronic kidney disease; CXCR4, chemokine receptor type 4; DGCR8, Di-George syndrome critical region gene 8 or Pasha; DM, diabetes mellitus; EMT, epithelial-to-mesenchymal transition; ER, endoplasmic reticulum; ERK-2, extracellular signal-regulated kinase 2; FGF-2, fibroblast growth factor 2; Foxo3, forkhead box O3; FSGS, focal segmental glomerulosclerosis; H2A. X, H2A histone family member X; HEK cell, human embryonic kidney cell; HepG2 cell, human hepatocellular liver carcinoma cell line; HIF-1α, hypoxia-inducible factor 1 alpha, HK-2 cell, human kidney 2 cell; HO-1, heme oxygenase-1; HPTEC, human proximal tubular epithelial cell; HUVEC, human umbilical vein endothelial cell; ICU, intensive care units; IGF1R, insulin-like growth factor 1 receptor; IL, interleukin; IKKb, inhibitor of NF-kB kinases b; IRAK-1, interleukin-1 receptor-associated kinase 1; IRI, ischemia-reperfusion injury; K2Cr2O7, potassium dichromate; LC3-II, light chain 3-II; MCP1, monocyte chemoattractant protein-1; MDM2, murine double-minute 2; miRNA, microRNA; mRNA, messenger RNA; NF-kB, nuclear factor-kappaB; NRK-52E cell, rat renal proximal tubular cell line; PDCD4, programmed cell death protein 4; Pparα, peroxisome proliferator activated receptor alpha; PTC, proximal tubular cell; PTEN, phosphatase and tensin homolog; Rab-11a, Ras-related proteins in brain 11 a; RISC, RNA-induced silencing complex; ROS, reactive oxygen species; S1PR1, sphingosine-1-phosphate receptor 1; SHRSP, stroke-prone spontaneously hypertensive rat; STZ, streptozocin; T, tissue; TEC, tubular epithelial cell; TEnC, tubular endothelial cell; TEpC, tubular epithelial cell; TNF, tumor necrosis factor; TGF-β, transforming growth factor beta; TRAF-6, TNF receptor-associated factor 6; Treg, regulator T cell; U, urine; UTR, untranslated region; UUO, unilateral ureteral obstruction; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; ZEB1/ZEB2, zinc finger E-box-binding homeobox
MicroRNAs; Acute kidney injury; Renal fibrosis
Acute kidney injury
Acute kidney injury (AKI) is a complex syndrome that
occurs in a variety of settings with clinical manifestations
ranging from a minimal elevation in serum creatinine to
anuric renal failure. AKI conveys significant morbidity
and mortality, is a major risk factor of chronic kidney
disease, and is thus associated with huge health and
socioeconomic burdens [
]. Despite research advances
in the past decades, however, the complex
pathophysiology of AKI is not fully understood. The regulatory
mechanisms underlying post-AKI repair and fibrosis
remain to be clarified. Furthermore, there is no definitively
effective treatment for AKI.
MicroRNA biogenesis and function
MicroRNAs (miRNAs) are endogenous single-stranded
noncoding mRNAs of 19~23 nucleotides. They were
first discovered in Caenorhabditis elegans by Ambros’s
group in 1993 [
] and show surprisingly high
conservation across species. The evidence accumulated over the
past two decades shows that miRNAs play a critical role
in the post-transcriptional regulation of almost all
biological cell functions, including proliferation,
differentiation, metabolism, and apoptosis [
]. miRNAs, which
are expressed in a tissue-specific manner, are
fundamental to normal development and physiology [
] and are
involved in the pathologic pathways of many disease
To date, more than 2000 miRNAs have been
discovered in the human genome. The miRNA-encoded genes
are found as either independent genes having their own
promoters, or as sequences in the introns of
proteincoding genes [
]. RNA polymerase II transcribes an
miRNA gene into a primary transcript (called a
primiRNA) of several kilobases that can encode either an
individual miRNA or a polycistronic cluster of two or
more miRNAs. The RNase III enzyme, DROSHA, and
its cofactor DGCR8 (Di-George syndrome critical region
gene 8 or Pasha), cleave a pri-miRNA at its stem-loop
structure, generating an approximately 70-nucleotide
intermediate called the pre-miRNA. Exportin-5 exports
the pre-miRNA from the nucleus to the cytoplasm, and
the RNase III enzyme, DICER, further cleaves it to yield
a single-stranded mature miRNA. To perform its
function, an miRNA is incorporated along with the
argonaute (AGO) protein to form an effector complex called
the RNA-induced silencing complex (RISC). RISC binds to
the 3′-untranslated region (UTR) of a target messenger
RNA (mRNA), leading to the repression of either protein
translation or mRNA degradation. Unlike small interfering
RNAs in plants, miRNAs do not require complete
complementarity to bind their targets. Instead, the evidence
suggests that the “seed sequence” (nucleotides 2 through 8 of
the miRNA) is the most important region for the ability of
an miRNA to bind and regulate its target gene(s). Once
bound, miRNAs induce repression by blocking the
initiation or elongation of translation or de-adenylating the
mRNA transcripts. Because miRNAs do not require
complete complementarity to repress gene expression,
a given miRNA can regulate multiple mRNA transcripts
and a given mRNA transcript can be repressed by
multiple miRNAs. It is estimated that miRNAs regulate
more than half of the protein-coding genes in human
]. Moreover, miRNAs have been implicated in various
human diseases [
], including kidney diseases, such
as polycystic kidney disease , renal cell carcinoma
], diabetic nephropathy [
], lupus nephritis, [
and renal allograft rejection [
]. In the past few years,
researchers have begun to address the relevance of
miRNAs to AKI.
miRNAs in acute kidney injury
The miRNAs that have been implicated in AKI are
summarized in Tables 1 and 2, and those with potential
pathological or protective roles are summarized in
Table 3. The first evidence of miRNAs having
pathological roles in AKI was reported by Wei et al. who
developed a Dicer-knockout mouse model, in which Dicer
was specifically deleted from proximal tubular cells. These
mice exhibit a global down-regulation of microRNAs in
the renal cortex. They have normal renal function and
histology under control conditions but show resistance to
the AKI that follows bilateral renal ischemia-reperfusion
(IRI). Under the latter conditions, Dicer-null mice show
significantly better renal function, less tissue damage, less
tubular apoptosis, and better survival than their wild-type
miR-10a is renal tubule-specific miRNA that is
released from kidney tissues upon injury. In rodent models
of renal IRI and streptozocin (STZ)-induced diabetic
nephropathy, the levels of miR-10a are increased decreased
in urine and kidney tissue, respectively [
is thought to exert protective actions during injury by
targeting IL-12/IL-23p40 and the pro-apoptotic protein
BIM . In humans, decreased plasma levels of
miR10a have been shown to predict AKI in critical patients
of intensive care units (ICUs) [
The members of the miR-17 family have been shown
to be induced by pro-inflammatory cytokines, and their
tissue expressions are increased in rodent models of
renal IRI [
miR-21 appears to play a dual role; on the one hand, it
protects against injury by inhibiting apoptosis and
inflammation; on the other hand, it may amplify the injury
response and promote fibrosis. Studies have shown that
miR-21 inhibits apoptosis by down-regulating
programmed cell death protein 4 (PDCD4), down-regulating
33, 52, 54
34, 45, 52
39, 45, 64
phosphatase and tensin homolog (PTEN), activating the
AKT pathway, up-regulating B cell lymphoma 2 (BCL-2),
and decreasing the levels of active caspase-3 and
caspase8 proteins [
]. Up-regulation of miR-21 also inhibits
inflammation by decreasing nuclear factor-kappaB
(NFkB), tumor necrosis factor (TNF), interleukin 6 (IL-6), and
IL-18, and by increasing IL-10 . Experimental
upregulation of miR-21 provides morphologic and functional
renoprotection in animal models of AKI [
]. miR-21 is
induced by transforming growth factor beta (TGF-β)/Smad,
hypoxia inducible factor 1 alpha (HIF-1α), TNF, and
fibroblast growth factor 2 (FGF-2) [
], and this miRNA
promotes fibrosis by targeting peroxisome
proliferatoractivated receptor alpha (Pparα) and altering lipid
metabolism . miR-21 also targets Mpv17l, a mitochondria
inhibitor of reactive oxygen species (ROS) [
inhibits autophagy by targeting Ras-related proteins in brain
11 a (Rab-11a), decreasing light chain 3-II (LC3-II),
decreasing beclin-1, and increasing p62 [
]. In vivo blockade
of miR-21 reduces renal fibrosis and macrophage
infiltration in animal models. Moreover, increased urinary and
plasma levels of miR-21 have been observed in various
clinical AKI settings [
26, 28, 29
]. For example, urine and
plasma miR-21 levels were shown to correlate with AKI
severity and hospital mortality and to predict the need for
postoperative renal replacement therapy [
one study found decreased, but not increased, expression
of miR-21 in AKI patients. Lower baseline plasma levels of
miR-21 have been demonstrated to predict cardiac
surgeryassociated AKI [
miR-24 is up-regulated in mouse kidney after IRI and
in patients after kidney transplantation. This miRNA
enhances apoptosis by down-regulating
sphingosine-1phosphate receptor 1 (S1PR1), H2A histone family
24, 26, 28, 29, 56
member X (H2A.X), and heme oxygenase-1 (HO-1).
Inhibition of miR-24 was shown to prevent renal injury in
animal models [
miR-26a represses IL-6 expression to promote the
expansion of regulator T cells (Tregs). The tissue levels of
miR-26a is down-regulated in animal models of AKI, and
experimental overexpression attenuates renal IRI and
improves renal recovery [
]. miR-26b is down-regulated in
the tissue and blood, yet up-regulated in the urine
]. Decreased blood levels of miR-26a and
miR27a predict AKI in the ICU. Decreased blood levels
of miR-26a and miR-27a prior to cardiac surgery also
predict AKI later on .
miR-29a is highly expressed in the kidney, where it
acts against fibrosis by suppressing collagen expression
in tubular cells. Decreased serum levels of miR-29a have
been shown to predict AKI in ICU patients, and
correlate with AKI severity [
miR-30c, which is essential for normal kidney
homoeostasis, targets several genes important for kidney
structure and function. miR-30c is up-regulated in the
tissue, blood, and urine obtained from animal models of
contrast nephropathy and IRI [
miR-30d, which is released to the urine from kidney
tissues following injury, down-regulates the apoptotic
proteins, caspase 3 and p53, and may provide protective
effects during IRI [
miR-101-3p is highly expressed in the kidney, and
decreased serum levels of this miRNA have been shown to
predict AKI in the ICU [
miR-122 is down-regulated in the mice kidneys of
mice subjected to cisplatin-induced AKI [
]. It exerts
anti-apoptotic effects by down-regulating forkhead box
miR-127a, which is induced by HIF-1α, participates in
protecting the cytoskeleton protection (by preventing
actin depolmerization), maintaining cell-matrix and
cell-cell adhesion maintenance (by preventing focal
adhesion complexes disassembly and tight junctions
disorganization), and promoting intracellular
trafficking (by targeting kinesin family member 3B) [
Decreased blood levels of miR-127a were shown to predict
AKI in the ICU. Decreased blood levels of miR-127a prior
to cardiac surgery were found be predict AKI later
miR-146a is down- and up-regulated in the blood and
kidney, respectively, during AKI. Decreased blood levels
have been shown to predict AKI in the ICU and correlate
with the severity of AKI [
]. It is induced by NF-kB and
exerts anti-inflammatory effect by down-regulating TNF
receptor-associated factor 6 (TRAF-6) and interleukin-1
receptor-associated kinase 1 (IRAK-1) [
miR-192 is enriched in kidneys and the small intestine.
It is induced by TGF-β during the stress response. It
promotes fibrosis by down-regulating SIP1. It also
downregulates E3 ubiquitin ligase and murine double-minute 2
(MDM2) and results in de-repression of p53 and G2/M
]. miR-194 is also enriched in kidneys and small
intestine. It is induced during the stress response, and its
levels in tissue, blood, and urine levels are increased
during AKI [
15, 38, 39
miR-199a exerts anti-inflammatory effect by
downregulating inhibitor of NF-kB kinases b (IKKb) [
exhibits anti-proliferatory effect by down-regulating the
proto-oncogene MET [
], and confers anti-apoptosis
effect by down-regulating extracellular signal–regulated
kinase 2 (ERK-2) and HIF-1α [
]. Therefore, it may
help limit kidney injury.
miR-126 and miR-296 have been identified in
microvesicles from endothelial progenitor cells and are thought to
exert renoprotective effects via their abilities to decrease
apoptosis and leukocyte infiltration, while promotes
angiogenesis and tubular cell proliferation [
overexpression of miR-126 enhances stromal cell-derived
factor 1/chemokine receptor type 4 (CXCR4) -dependent
vasculogenic progenitor cell mobilization and promotes
vascular integrity and supports renal recovery after IRI [
Decreased serum levels of miR-126 have been shown to
predict AKI in ICU patients, and correlate with the severity
of AKI [
Members of the miR-200 family are highly expressed
in tubular structures such as renal tubules, lungs, the
small intestine, and various exocrine glands. miR-200b
and miR-200c have been proposed to be anti-fibrotic.
They down-regulate TGFβR1 and zinc finger
E-boxbinding homeobox (ZEB1/ZEB2), which are
transcriptional repressors of E-cadherin, and thereby prevent the
epithelial-to-mesenchymal transition (EMT) induced by
miR-210 is induced by HIF1-α and released by renal
endothelial cell. It regulates angiogenesis by
downregulating ephrin-A3 and up-regulating vascular
endothelial growth factor (VEGF) and vascular endothelial
growth factor receptor 2 (VEGFR2). It also regulates
mitochondria ROS production. Increased blood levels
of miR-210 was shown to predict post-AKI mortality in
critically ill patients [
]. In another study, decreased
blood levels of miR-210 were shown to predict AKI in the
ICU and correlate with the severity of AKI [
miR-214 is induced by TGF-β and promotes fibrosis; it
has been shown to down-regulate PTEN, up-regulate
the AKT pathway and inhibit apoptosis of monocytes
and macrophages. miR-214 is up-regulated in various
models of AKI and renal fibrosis [
24, 45, 47
] as well as
in monocytes of animal with chronic kidney disease.
Experimental antagonism of miR-214 has been shown to
ameliorate renal fibrosis [
miR-494 is up-regulated early in AKI, with increased
urine levels detected in rodent models of renal IRI and
patients with AKI. It has been reported to promote
apoptosis and inflammation by down-regulating activating
transcription factor 3 (ATF3) and increasing IL-6, monocyte
chemoattractant protein-1 (MCP-1), p-selectin [
Pathway analysis has suggested that it also targets adiponectin
receptor 2 (ADIPOR2), BCL-2 facilitator, and insulin-like
growth factor 1 receptor (IGF1R), which would increase
inflammation and lead to more damage. However,
miR494 also targets pro-apoptotic proteins in the AKT
pathway, and to exert protective effects. The mechanism
responsible for regulating the balance between these
antiand pro- apoptotic effects requires further study.
Finally, miR-687 is induced by HIF-1, and enhances
apoptosis by down-regulating PTEN. Animal studies have
shown that miR-687 blockade preserves PTEN expression
and attenuates cell cycle activation and decreases
apoptosis, resulting in protection against kidney injury [
Many miRNAs have been implicated in the AKI. Some
of them contribute to the pathogenesis by regulating
apoptosis and inflammation, to amplifying or reduce
acute injury responses, while others regulate fibrosis and
angiogenesis, to participate in renal recovery or the
progression to fibrosis. The biological and pathological
functions of many miRNAs in AKI are still not fully understood
in AKI. Some studies have yielded inconsistent data
regarding the expression pattern of miRNAs across different
samples, species, disease models, and time points. These
discrepancies warrant investigations.
In addition to their tissue expressions, miRNAs may
be detected in various extracellular human body fluids,
such as serum, urine, saliva, and cerebral spinal fluid.
miRNAs are contained in exosomes and may remained
stable over prolonged periods. They may be specifically
up-regulated or down-regulated in response to injury
signals and/or released into body fluids from resident
tissues. Certain miRNAs have been investigated for their
potential to serve as novel biomarkers for the early
detection or prognostication of AKI. Given the complex
pathophysiology and the dynamic nature of AKI, an
miRNA panel may be more feasible rather than a single
miRNA. Further validation studies are needed to
evaluate the clinical utility of such a panel.
Some miRNAs may be potential therapeutic targets
for AKI. Recently, an miRNA inhibitor has been proven
to successfully suppress the replication of hepatitis C
virus in a clinical trial [
]. Systemic or local
administration of specific miRNAs mimics or antagonists in vivo
could offer a strategy for preventing or ameliorating AKI
or barring its progression to chronic kidney disease.
In the post-genome era, miRNAs are promising rising
stars in translational medicine as they offer the potential
to guide the individualized diagnosis and treatment of
human diseases including AKI.
This work was supported by the Chang Gung Memorial Hospital Research
Program grant CMRPG3D1452, CMRPG 3F0561, CMRPG1B0581 and
CIRPG3B0042.; Ministry of Science and Technology 104-2314-B-182A-131 and
Availability of data and materials
The manuscript was written by PCF. All authors critically revised the
manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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