Open Access

MicroRNAs in acute kidney injury

Human Genomics201610:29

https://doi.org/10.1186/s40246-016-0085-z

Received: 16 July 2016

Accepted: 31 August 2016

Published: 8 September 2016

Abstract

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.

Keywords

MicroRNAs Acute kidney injury Renal fibrosis

Background

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 [1, 2]. 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 [3] 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 [4]. miRNAs, which are expressed in a tissue-specific manner, are fundamental to normal development and physiology [4] and are involved in the pathologic pathways of many disease models.

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 protein-coding genes [5]. RNA polymerase II transcribes an miRNA gene into a primary transcript (called a pri-miRNA) 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 [6]. Moreover, miRNAs have been implicated in various human diseases [7, 8], including kidney diseases, such as polycystic kidney disease [9], renal cell carcinoma [10], diabetic nephropathy [11], lupus nephritis, [12] and renal allograft rejection [13]. 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 counterparts [14].
Table 1

miRNAs implicated in acute kidney injury

miRNA

Samples

Species

Model

Expression

Reference

k12-3

In vitro

HK-2 cells

Oxidative stress

Down then up

[51]

let-7a

T, B

Rat, human

Contrast nephropathy, contrast nephropathya

Down

[52]

let-7a-1-3p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

let-7a-2*

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

let-7b

B

Human

ICU AKIa

Down

[46]

let-7d

U

Rat

Gentamicin nephropathy

Down

[53]

let-7e

T, in vitro

Mouse, HK-2 cells

IRI

Up, down

[23, 54]

let-7f

B, T

Human, mouse

ICU AKIa, IRI

Down

[34, 46]

let-7g

T, U

Mouse, rat

Cisplatin nephropathy

Up, down

[33, 35]

miR-7

T, in vitro

Mouse, HK-2 cells

IRI, oxidative stress

Up

[14, 51]

miR-7a-1-3p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-10a

T, U, B

Mouse, human, rat

IRI, DM-CKD (STZ), FSGSa, ICU AKIa

Up, down

[15, 16, 18]

miR-10b*

T

Mouse

Cisplatin nephropathy

Down

[35]

miR-15

U

Rat

Cisplatin nephropathy

Up

[55]

miR-15b-5p

T, in vitro

Mouse, HK-2 cells

IRI

Down

[54]

miR-16

B, U

Human, rat

ICU AKIa, cisplatin nephropathy

Up, down

[46, 55]

miR-17-3p

T

Mouse

IRI

Up

[14, 49]

miR-17-5p

T, U

Mouse, rat

IRI, cisplatin nephropathy

Up, down

[19, 20, 33]

miR-18a

T, B, U, in vitro

Mouse, rat, human, HPTECs

IRI, gentamicin nephropathy, folic acid, CdCl2, arsenic trioxide, AA, K2Cr2O7, cisplatin, UUO, allograft rejectiona, renal fibrosisa

Up, down

[14, 34, 47, 56, 57]

miR-19a

T

Mouse

IRI

Up

[34]

miR-20a

T, in vitro, U

Mouse, TECs, rat, HK-2 cells

Cisplatin nephropathy, IRI

Up, down

[37, 54, 55]

miR-20b-5p

T, U, in vitro

Rat, mouse, HK-2 cells

Cisplatin nephropathy, IRI

Up (urine), down (tissue)

[33, 54]

miR-21

B, U, T, in vitro

Human, rat, mouse, TEC, CRL-2753 cells, NRK52E cells, HK-2 cells

IRI, TGF-β, anti-Thy 1.1, UUO, SHRSP, gentamicin nephropathy, folic acid, CdCl2, arsenic trioxide, AA, K2Cr2O7, allograft rejectiona, renal fibrosisa, AKIa

Up, down

[1930, 34, 37, 45, 5658]

miR-24

B, T, in vitro

Human, rat, CRL-2753 cells, NRK52E cells, HK-2 cells, HUVECs

ICU AKIa, transplantationa, UUO, IRI

Up, down

[31, 45, 46]

miR-24-2

T

Mouse

IRI

Up

[34]

miR-25-3p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-26a

In vitro, T

HK-2 cells, mouse

IRI, oxidative stress, cisplatin nephropathy

Down

[32, 35, 51]

miR-26b

T, in vitro, U, B

Rat, CRL-2753 cells, NRK52E cells, human

UUO, cisplatin nephropathy, ICU AKIa

Down (tissue, blood), up (urine)

[18, 33, 45]

miR-27a-3p

B

Human

ICU AKIa

Down

[18]

miR-29a

T, in vitro, B

HK-2 cells, human

Oxidative stress, ICU AKIa

Up, down

[18, 51, 59]

miR-29b

T, in vitro

Rat, HK-2 cells

Oxidative stress

Up

[51, 59]

miR-29c

T

Mouse

IRI

Up

[34, 59]

miR-30a-5p

T, U, in vitro, B

Rat, mouse, HK-2 cells, human

Cisplatin nephropathy, IRI, contrast-induced nephropathy, contrast-induced nephropathya

Up (urine, blood, tissue), down (tissue)

[33, 52, 54]

miR-30c

T, in vitro, B

Rat, CRL-2753 cells, NRK52E cells, mouse, human

TGF-β, UUO, SHRSP, contrast-induced nephropathy, contrast-induced nephropathya

Up, down

[34, 45, 52]

miR-30c-1

T

Mouse

IRI

Up

[34]

miR-30c-2*

In vitro

HK-2 cells

Oxidative stress

Down

[51]

miR-30d

T, U, B

Mouse, human

IRI, DM-CKD (STZ), FSGSa

Up, down, unchanged

[16]

miR-30d*

B

Human

ICU AKIa

Down

[46]

miR-30e

T, B

Mouse, rat, human

Cisplatin nephropathy, contrast-induced nephropathy, contrast-induced nephropathya

Up, down

[35, 52]

miR-34a

T, in vitro

Mouse, BUMPT-306 cells, NRK-52E cells, RTECs

Cisplatin nephropathy, IRI

Up

[35, 60, 61]

miR-34b

T

Mouse

IRI

Up

[47]

miR-92a

T

Mouse

IRI

Up

[34]

miR-92b*

B

Human

ICU AKIa

Up

[46]

miR-93-3p

B

Human

ICU AKIa, AKI post-cardiac surgerya

Down

[18]

miR-93-5p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-99b

In vitro, T

HK-2 cells, mouse

ER stress, IRI

Down

[51, 54]

miR-101-3p

B

Human

ICU AKIa

Down

[18]

miR-101a

T, in vitro

Mouse, HK-2 cells

UUO

Down

[25]

miR-106a-5p

T, in vitro

Mouse, HK-2 cells, primary PTCs, rat

IRI, AA nephropathy

Up, down

[19, 20, 38]

miR-122

T

Mouse

Cisplatin nephropathy, IRI

Down

[35, 49]

miR-123

T

Mouse

IRI

Up

[49]

miR-125a-5p

T, in vitro

Mouse, HK-2 cells

IRI

Down

[54]

miR-125b

T, in vitro

Mouse, HepG2 cells, HEK293 cells, NRK52E cells

Cisplatin nephropathy

 

[62]

miR-126-3p

B

Human

ICU AKIa

Down

[18]

miR-126-5p

T, in vitro

Mouse, rat, TEnCs, TEpCs

IRI

Up

[34, 43, 44, 63]

miR-127-3p

T, in vitro, B

Rat, mouse, NRK-52E cells, HK-2 cells, human

IRI, ICU AKIa, AKI post-cardiac surgerya

Up, down

[14, 18, 36, 49]

miR-129-3p

T

Mouse

IRI

Up

[34]

miR-129-5p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-130b-3p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-132

T, in vitro

Mouse, human, HPTECs

IRI, folic acid, CdCl2, arsenic trioxide, AA, K2Cr2O7, cisplatin, UUO, allograft rejectiona, renal fibrosisa

Up

[14, 57]

miR-133a

In vitro

HK-2 cells

ER stress

Down

[51]

miR-134

T

Mouse

IRI

Up

[47]

miR-135b

T

Mouse

IRI

Down

[14, 49]

miR-140-3p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-141

T

Mouse

IRI

Up

[34]

miR-142-3p

T, in vitro

Mouse, HK-2 cells

UUO

Up

[25]

miR-142-5p

T, in vitro

Mouse, HK-2 cells

UUO

Up

[25]

miR-145

T, in vitro

Rat, mouse, CRL-2753 cells, NRK52E cells, CD133+ renal medullary progenitor cells

TGF-β, SHRSP salt challenge

Up, down

[39, 45, 64]

miR-146a

T, in vitro, B

Mouse, TECs, human

IRI, ICU AKIa

Down (blood), up (tissue)

[18, 37]

miR-146b-5p

T, in vitro

Mouse, human, HPTECs

IRI, folic acid, CdCl2, arsenic trioxide, AA, K2Cr2O7, cisplatin, UUO, allograft rejectiona, renal fibrosisa

Up

[57]

miR-149

T

Mouse

IRI

Down

[34]

miR-150

T, in vitro

Mouse, immortalized mouse cardiac endothelial cell lines

IRI, AMI using LAD ligation

Down

[65]

miR-155

B, U, T, in vitro

Rat, human, mouse, HK-2 cells

IRI, gentamicin nephropathy, Cisplatin nephropathy, AKIa

Up, down

[54, 56, 66]

miR-181a*

In vitro

HK-2 cells

ER stress

Up

[51]

miR-181a-2*

In vitro

HK-2 cells

ER stress

Down

[51]

miR-181d

T

Mouse

IRI

Down

[34]

miR-182

T

Mouse

IRI

Up

[47]

miR-183-5p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-187

T, in vitro

Mouse, TECs

IRI

Down

[37]

miR-188-5p

T

Mouse

IRI

Up

[34]

miR-191a-5p

T, U

Rat

Cisplatin nephropathy

Up (urine), down (tissue)

[33]

miR-192

T, in vitro, B, U

Mouse, rat, CRL-2753 cells, NRK52E cells, TECs, HK-2 cells, primary PTCs

IRI, UUO, SHRSP, AA nephropathy, cisplatin nephropathy, contact freezing, Dahl salt-sensitive rat with high salt administration

Up, down

[15, 33, 45, 55]

miR-193

T, in vitro, U

Mouse, HK-2 cells, Rat

UUO, cisplatin nephropathy

Down (tissue), up (urine)

[25, 33, 35, 55]

miR-194

T, in vitro, B, U

Mouse, rat, TECs, HK-2 cells, primary PTCs

IRI, AA nephropathy, contact freezing, Dahl salt-sensitive rat with high salt administration

Up, down

[15, 3739]

miR-197

T

Mouse

IRI

Down

[34]

miR-199a-3p

T, in vitro

Mouse, TECs

IRI

Up

[37]

miR-200a

T, B, U

Human, Rat, mouse

Contact freezing, Dahl salt-sensitive rat with high salt administration, contrast-induced nephropathy, contrast-induced nephropathya

Up, down

[39, 52]

miR-200b

T, in vitro, B, U

Rat, CRL-2753 cells, NRK52E cells, human

TGF-β, UUO, contact freezing, early CKD (Dahl salt-sensitive rat with high salt administration)

Up, down

[34, 39, 45]

miR-200c

T, in vitro, U, B

Rat, CRL-2753 cells, NRK52E cells, human

TGF-β, contact freezing, early CKD (Dahl salt-sensitive rat with high salt administration), ICU and transplant AKIa

Up, down

[29, 39, 45]

miR-202

In vitro

HK-2 cells

ER stress

Down

[51]

miR-203

U

Rat

Gentamicin nephropathy

Down

[53]

miR-205

In vitro

HK-2 cells, primary PTCs

Oxidative stress, ER stress, AA nephropathy

Down

[38, 51]

miR-207

T

Mouse

IRI

Up, down

[14, 34]

miR-210

B, T, in vitro, U

Human, mouse, HUVEC-12 cells, HK-2 cells, primary PTCs, rat

IRI, Oxidative stress, AA nephropathy, cisplatin nephropathy, ICU AKIa

Up, down

[18, 34, 38, 46, 47, 51, 55]

miR-211

T

Mouse

IRI

Down

[34]

miR-212

T

Mouse, human, HPTECs

IRI, folic acid, CdCl2, arsenic trioxide, AA, K2Cr2O7, cisplatin, UUO, allograft rejectiona, renal fibrosisa

Up, down

[34, 57]

miR-214

T, in vitro

Mouse, rat, HK-2 cells, TECs, CRL-2753 cells, NRK52E cells, human

TGF-β, anti-Thy 1.1, UUO, SHRSP, IRI, diabetic nephropathya

Up

[2325, 37, 45, 47]

miR-215

In vitro

HK-2 cell

ER stress

Down

[51]

miR-218

T, in vitro

Mouse, HK-2 cells

UUO

Down

[25]

miR-218-1

T

Mouse

IRI

Up

[34]

miR-218a-5p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-221*

In vitro

HK-2 cells

Oxidative stress

Up

[51]

miR-223

T, in vitro

Mouse, HK-2 cells

UUO

Up

[25]

miR-290-3p

T

Mouse

IRI

Up

[34]

miR-296

T, in vitro

Rat, mouse, TEnCs, TEpCs

IRI

Up, down

[14, 43]

miR-302b

T

Mouse

IRI

Up

[34]

miR-302c

T

Mouse

IRI

Up

[34]

miR-320

B, T, U

Human, mouse, rat

IRI, cisplatin nephropathy, gentamicin nephropathy, contrast-induced nephropathy, ICU AKIa, contrast-induced nephropathya

Up, down

[23, 33, 34, 46, 52, 53]

miR-322

T

Mouse

IRI

Down

[14]

miR-324-3p

T

Mouse

IRI

Down

[14]

miR-326

T

Mouse

IRI

Down

[34]

miR-328

T

Mouse

IRI

Down

[34]

miR-328a-3p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-329

T, in vitro

Rat, CRL-2753 cells, NRK52E cells

UUO

Down

[45]

miR-335

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-340-5p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-346

T

Mouse

IRI

Down

[34]

miR-362-5p

T

Mouse

IRI

Up

[14, 34]

miR-365*

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-378a-5p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-379

T

Mouse

IRI

Down

[14, 49]

miR-382

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

miR-423

U

Human

ICU and transplant AKIa

Up

[29]

miR-449

In vitro

NRK-52E cells

Cisplatin nephropathy

Up

[67]

miR-450a-3p

T, in vitro

Mouse, HK-2 cells, primary PTCs

IRI, AA nephropathy

Up, down

[34, 38]

miR-451

T

Mouse

IRI

Up

[34]

miR-455-3p

T

Mouse

IRI

Down

[14]

miR-466a-5p

T

Mouse

IRI

Up

[34]

miR-466b-5p

T

Mouse

IRI

Up

[34]

miR-466c-5p

T

Mouse

IRI

Down

[34]

miR-466f-3p

T

Mouse

IRI

Down

[34]

miR-466g

T

Mouse

IRI

Down

[34]

miR-466i

T

Mouse

IRI

Down

[34]

miR-467

T

Mouse

IRI

Up

[14]

miR-467a

T

Mouse

IRI

Down

[34]

miR-467b

T

Mouse

IRI

Down

[34]

miR-467e

T

Mouse

IRI

Down

[34]

miR-467f

T

Mouse

IRI

Down

[34]

miR-467g

T

Mouse

IRI

Down

[34]

miR-468

T

Mouse

IRI

Down

[34]

miR-483

T

Mouse

IRI

Up, down?

[34]

miR-484

T

Mouse

IRI

Down

[34]

miR-486

T

Mouse

IRI

Up

[14]

miR-487b

T

Mouse

IRI

Down

[14]

miR-489

T

Mouse

IRI

Up

[14]

miR-491

T

Mouse

IRI

Down

[14]

miR-494

T, U, B

Mouse, human

IRI, ICU AKIa

Up, unchanged

[48]

miR-495

T

Mouse

IRI

Up

[14]

miR-503

In vitro

HK-2 cells

ER stress

Down

[51]

miR-532-3p

T, U

Mouse, rat

IRI, Cisplatin nephropathy

Up, down

[33, 34]

miR-542-3p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

miR-547-3p

T

Mouse

IRI

Down

[34]

miR-574-5p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-617

B

Human

ICU AKIa

Up

[46]

miR-620

B

Human

ICU AKIa

Down

[46]

miR-625*

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-630

In vitro

HK-2 cells

Oxidative stress

Up

[51]

miR-638

B

Human

ICU AKIa

Up

[46]

miR-663b

B

Human

ICU AKIa

Up

[46]

miR-668

T

Mouse

IRI

Up

[14]

miR-669a

T

Mouse

IRI

Down

[34]

miR-669f

T

Mouse

IRI

Down

[34]

miR-669h-3p

T

Mouse

IRI

Down

[34]

miR-671-3p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-671-5p

T

Mouse

IRI

Up

[34]

miR-674

T

Mouse

IRI

Down

[34]

miR-680

T

Mouse

IRI

Up

[34]

miR-684

T

Mouse

IRI

Up

[34]

miR-685

T

Mouse

IRI

Up

[14, 34, 49]

miR-687

T, in vitro

Mouse, BUMPT-306 cells, HEK cells

IRI

Up

[14, 49]

miR-689

T

Mouse

IRI

Up

[34]

miR-694

T

Mouse

IRI

Up

[14]

miR-705

T

Mouse

IRI

Up

[34]

miR-708

T

Mouse

IRI

Up

[34]

miR-714

T, B

Mouse

IRI

Up

[68]

miR-718

T

Mouse

IRI

Down

[34]

miR-721

T

Mouse

IRI

Up

[34]

miR-744-5p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-805

T, in vitro

Mouse, TECs

IRI

Down

[34, 37]

miR-875-5p

T

Mouse

IRI

Down

[34]

miR-876-5p

T

Mouse

IRI

Up

[34]

miR-877

T

Mouse

IRI

Up, down?

[34]

miR-877*

T, B

Mouse

IRI

Up

[68]

miR-1187

T

Mouse

IRI

Down

[34]

miR-1188

T, B

Mouse

IRI

Up

[68]

miR-1196

T

Mouse

IRI

Down

[34]

miR-1198

T

Mouse

IRI

Down

[34]

miR-1224

T, B

Mouse

IRI

Up

[68]

miR-1244

B

Human

ICU AKIa

Down

[46]

miR-1249

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

miR-1839-5p

T, U

Rat

Cisplatin nephropathy

Up (urine),down (tissue)

[33]

miR-1892

T

Mouse

IRI

Up

[34]

miR-1894-3p

T

Mouse

IRI

Up

[34]

miR-1897-3p

T, B

Mouse

IRI

Up

[68]

miR-4521

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Down

[38]

miR-4640

U

Human

ICU and transplant AKIa

Down

[29]

miR-4716-5p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

miR-4730

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

miR-4747-3p

In vitro

HK-2 cells, primary PTCs

AA nephropathy

Up

[38]

aHuman studies

Table 2

miRNAs implicated in human studies related to kidney injury

miRNA

Kidney injury

Expression

Reference

Up

Down

hsa-let-7b

AKI in ICU

 

Blood

[46]

hsa-let-7f

AKI in ICU

 

Blood

[46]

hsa-miR-10a

Focal segmental sclerosis

Urine

 

[16]

AKI in ICU

 

Blood

[18]

hsa-miR-16

AKI in ICU

 

Blood

[46]

hsa-miR-21

AKI, chronic renal allograft dysfunction, renal allograft rejection, renal fibrosis

Tissue, blood, urine

 

[24, 26, 28, 29, 56]

AKI after cardiac surgery

 

Blood

[30]

hsa-miR-24

AKI in ICU

 

Blood

[46]

Transplanted renal graft with prolonged cold ischemia time

Tissue

 

[31]

hsa-miR-26b

AKI in ICU

 

Blood

[18]

hsa-miR-27a-3p

AKI in ICU

 

Blood

[18]

hsa-miR-29a

AKI in ICU

 

Blood

[18]

hsa-miR-30a-5p

Contrast-induced nephropathy

Blood

 

[52]

hsa-miR-30c

Contrast-induced nephropathy

Blood

 

[52]

hsa-miR-30d

Focal segmental sclerosis

Urine

 

[16]

hsa-miR-30d*

AKI in ICU

 

Blood

[46]

hsa-miR-30e

Contrast-induced nephropathy

Blood

 

[52]

hsa-miR-92b*

AKI in ICU

Blood

 

[46]

hsa-miR-93-3p

AKI in ICU, AKI post-cardiac surgery

 

Blood

[18]

hsa-miR-101-3p

AKI in ICU

 

Blood

[18]

hsa-miR-126-3p

AKI in ICU

 

Blood

[18]

hsa-miR-127-3p

AKI in ICU, AKI post-cardiac surgery

 

Blood

[18]

hsa-miR-146a

AKI in ICU

 

Blood

[18]

hsa-miR-155

AKI

Urine

 

[56]

hsa-miR-200c

AKI in ICU, AKI in renal transplant

Urine

 

[29]

hsa-miR-210

AKI in ICU

Blood

 

[46]

AKI in ICU

 

Blood

[18]

hsa-miR-214

Diabetes related chronic kidney disease stage 4

Tissue

 

[24]

hsa-miR-320

AKI in ICU

 

Blood

[46]

hsa-miR-423

AKI in ICU, AKI in renal transplant

Urine

 

[29]

hsa-miR-494

AKI in ICU

Urine

 

[48]

hsa-miR-617

AKI in ICU

Blood

 

[46]

hsa-miR-620

AKI in ICU

 

Blood

[46]

hsa-miR-638

AKI in ICU

Blood

 

[46]

hsa-miR-663b

AKI in ICU

Blood

 

[46]

hsa-miR-1244

AKI in ICU

 

Blood

[46]

hsa-miR-4640

AKI in ICU, AKI in renal transplant

 

Urine

[29]

Table 3

Functional roles of miRNAs in acute kidney injury

Protective

Pathogenic

Kidney enriched, released from injured kidney tissues

Anti-inflammation

 miR-10a

 miR-21

 miR-26a

 miR-126

 miR-146a

 miR-199a

 miR-296

Anti-apoptosis

 miR-10a

 miR-21

 miR-122

 miR-126

 miR-199a

 miR-296

 miR-494

Anti-fibrosis

 miR-29a

 miR-200b

 miR-200c

Pro-angiogenesis

 miR-126

 miR-210

 miR-296

Enhancing tubular proliferation

 miR-126

 miR-296

Cytoskeleton, cell-matrix, cell-cell adhesion, cell trafficking

 miR-127a

Pro-inflammation

 miR-21

 miR-214

 miR-494

Pro-apoptosis

 miR-24

 miR-192

 miR-494

 miR-687

Pro-fibrosis

 miR-21

 miR-192

 miR-214

miR-10a

miR-30c

miR-30d

miR-200 family

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 [15, 16]. miR-10a is thought to exert protective actions during injury by targeting IL-12/IL-23p40 and the pro-apoptotic protein BIM [17]. In humans, decreased plasma levels of miR-10a have been shown to predict AKI in critical patients of intensive care units (ICUs) [18].

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 [19, 20].

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 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 caspase-8 proteins [21, 22]. Up-regulation of miR-21 also inhibits inflammation by decreasing nuclear factor-kappaB (NF-kB), tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-18, and by increasing IL-10 [21]. Experimental up-regulation of miR-21 provides morphologic and functional renoprotection in animal models of AKI [2123]. 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) [24, 25], and this miRNA promotes fibrosis by targeting peroxisome proliferator-activated receptor alpha (Pparα) and altering lipid metabolism [26]. miR-21 also targets Mpv17l, a mitochondria inhibitor of reactive oxygen species (ROS) [26]. miR-21 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 [27]. 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 [28]. Interestingly, 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 surgery-associated AKI [30].

miR-24 is up-regulated in mouse kidney after IRI and in patients after kidney transplantation. This miRNA enhances apoptosis by down-regulating sphingosine-1-phosphate receptor 1 (S1PR1), H2A histone family member X (H2A.X), and heme oxygenase-1 (HO-1). Inhibition of miR-24 was shown to prevent renal injury in animal models [31].

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 [32]. miR-26b is down-regulated in the tissue and blood, yet up-regulated in the urine [18, 33]. Decreased blood levels of miR-26a and miR-27a predict AKI in the ICU. Decreased blood levels of miR-26a and miR-27a prior to cardiac surgery also predict AKI later on [18].

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 [18].

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 [34].

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 [16].

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 [18].

miR-122 is down-regulated in the mice kidneys of mice subjected to cisplatin-induced AKI [35]. It exerts anti-apoptotic effects by down-regulating forkhead box O3 (Foxo3).

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) [36]. 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 on [18].

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 [18]. 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) [37].

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 down-regulates E3 ubiquitin ligase and murine double-minute 2 (MDM2) and results in de-repression of p53 and G2/M arrest [38]. 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 down-regulating inhibitor of NF-kB kinases b (IKKb) [40], exhibits anti-proliferatory effect by down-regulating the proto-oncogene MET [41], and confers anti-apoptosis effect by down-regulating extracellular signal–regulated kinase 2 (ERK-2) and HIF-1α [41, 42]. 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 [43]. Hematopoietic 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 [44]. Decreased serum levels of miR-126 have been shown to predict AKI in ICU patients, and correlate with the severity of AKI [18].

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-box-binding homeobox (ZEB1/ZEB2), which are transcriptional repressors of E-cadherin, and thereby prevent the epithelial-to-mesenchymal transition (EMT) induced by TGF-β [45].

miR-210 is induced by HIF1-α and released by renal endothelial cell. It regulates angiogenesis by down-regulating 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 [46]. In another study, decreased blood levels of miR-210 were shown to predict AKI in the ICU and correlate with the severity of AKI [18].

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 [24].

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 [48]. 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, miR-494 also targets pro-apoptotic proteins in the AKT pathway, and to exert protective effects. The mechanism responsible for regulating the balance between these anti- and 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 [49].

Conclusions

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 [50]. 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.

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

MCP-1: 

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

Declarations

Acknowledgements

Not applicable.

Funding

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 105-2314-B-182A-121.

Availability of data and materials

Not applicable.

Authors’ contributions

The manuscript was written by PCF. All authors critically revised the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Medical Center
(2)
Graduate Institute of Clinical Medical Sciences, Chang Gung University
(3)
Molecular Medicine Research Center, Chang Gung University
(4)
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University
(5)
Healthcare Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University
(6)
Heart Failure Center, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University
(7)
Department of Cardiology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University

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