Therapeutic effects of micro-RNAs in preclinical studies of acute kidney injury: a systematic review and meta-analysis

Abstract

AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently inhibiting protein expression, and pre-clinical studies have explored their roles in AKI. We conducted a systematic review and meta-analysis of miRNAs as therapeutics in pre-clinical AKI. Study screening, data extraction, and quality assessments were performed by 2 independent reviewers. Seventy studies involving 42 miRNA species were included in the analysis. All studies demonstrated significant effects of the miRNA intervention on kidney function and/or histology, with most implicating apoptosis and phosphatase and tensin homolog (PTEN) signaling. Fourteen studies (20.0%) examined the effect of miRNA-21 in AKI, and meta-analysis demonstrated significant increases in serum creatinine and kidney injury scores with miR-21 antagonism and pre-conditioning. No studies reported on adverse effects of miRNA therapy. Limitations also included lack of model diversity (100% rodents, 61.4% ischemia-reperfusion injury), and predominance of male sex (78.6%). Most studies had an unclear risk of bias, and the majority of miRNA-21 studies were conducted by a single team of investigators. In summary, several miRNAs target kidney function and apoptosis in pre-clinical AKI models, with data suggesting that miRNA-21 may mediate protection and kidney repair.Systematic review registration ID: CRD42019128854.

Figure 1

PRISMA flowchart. Number of titles, abstracts and full texts screened, resulting in 70 studies included in the qualitative synthesis. AKI = Acute kidney injury.

Figure 2

Study characteristics. Distribution of studies by (a) species and sex of rodents, (b) AKI model (IRI, ischemia–reperfusion injury), (c) Types of interventions used in the included studies (EV, extracellular vesicle; LNA, locked nucleic acid), and (d) Number of studies (n) per miRNA; further definition of miRNAs provided in some studies is designated in parenthesis.

Figure 3

Schematic representation of main biologic processes and signaling pathways in included studies. Apoptosis was the most common biologic process targeted by the interventions and PTEN/PI3K/AKT was the main pathway. AKT: Protein kinase B, HIF: Hypoxia-inducible factor, NF-κB: nuclear factor kappa B, NLRP3: Nod-like receptor family pyrin domain containing 3, PI3K: Phosphoinositide 3-kinase, PTEN: phosphatase and tensin homolog, and TLR: Toll-like receptor.

Figure 4

Meta-analyses of miRNA-21 antagonism on serum creatinine in AKI models (in the presence or absence of pre-conditioning). SD, standard deviation; CI, confidence interval.

Figure 5

Meta-analyses of miRNA-21 antagonism on injury scores in AKI models (in the presence or absence of pre-conditioning). SD, standard deviation; CI, confidence interval.

Figure 6

Risk of bias for the 70 included studies, using the SYRCLE ROB tool. Low risk of bias is represented in green, unclear risk in orange and high risk of bias in red.