Application of small RNA sequencing to identify microRNAs in acute kidney injury and fibrosis

Pellegrini, Kathryn L.; Gerlach, Cory V.; Craciun, Florin L.; Ramachandran, Krithika; Bijol, Vanesa; Kissick, Haydn; Vaidya, Vishal S.

doi:10.1016/j.taap.2015.12.002

Cited by 51 publications

(33 citation statements)

References 31 publications

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“…Small RNA sequencing revealed miR-15, miR-383-5p and miR-146b-5p as top upregulated candidates. Interestingly, miR-15 is described to play a role in apoptosis by targeting Bcl2 in chronic lymphocytic leukemia (CLL) 32 and mir-146b-5p was found to be induced in AKI and fibrosis 33 . Top downregulated small RNA candidates in our sequencing analysis were Gm24706, miR-7046-3p and miR-203-5p.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury

Kölling

Genschel

Kaucsár

et al. 2018

Sci Rep

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Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Non-coding RNAs are crucially involved in its pathophysiology. We identified hypoxia-induced long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) to be upregulated in renal I/R injury. We here elucidated the functional role of Malat1 in vitro and its potential contribution to kidney injury in vivo. Malat1 was upregulated in kidney biopsies and plasma of patients with AKI, in murine hypoxic kidney tissue as well as in cultured and ex vivo sorted hypoxic endothelial cells and tubular epithelial cells. Malat1 was transcriptionally activated by hypoxia-inducible factor 1-α. In vitro, Malat1 inhibition reduced proliferation and the number of endothelial cells in the S-phase of the cell cycle. In vivo, Malat1 knockout and wildtype mice showed similar degrees of outer medullary tubular epithelial injury, proliferation, capillary rarefaction, inflammation and fibrosis, survival and kidney function. Small-RNA sequencing and whole genome expression analysis revealed only minor changes between ischemic Malat1 knockout and wildtype mice. Contrary to previous studies, which suggested a prominent role of Malat1 in the induction of disease, we did not confirm an in vivo role of Malat1 concerning renal I/R-injury.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury

Kölling

Genschel

Kaucsár

et al. 2018

Sci Rep

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“…Several rodent studies have demonstrated that drug-induced kidney injury is associated with increased expression of p53-responsive miR-34a, and this miRNA has been shown to suppress autophagy in tubular epithelial cells in a mouse model of ischemia/reperfusion-induced acute kidney injury [ 40 , 41 , 42 , 43 ]. The expression of miR-146-5p was shown to be increased with fibrosis in a mouse model of folic-acid-induced kidney injury, and in mouse models of ischemia/reperfusion injury and unilateral urethral obstruction-induced fibrosis [ 44 ]. Additionally, miR-146-5p expression was increased in human renal cortices with documented severe kidney injury or fibrosis [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

Fay

Alt

Ryba

et al. 2018

Toxics

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Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl2 (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, β2 microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury.

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“…Nonetheless, some efforts have been initiated through temporal miRNA sequencing experiments following AKI to identify miRNAs that are elevated during periods of repair. Our lab recently conducted small RNA sequencing in mice subjected to folic acid-induced nephropathy and identified 108 miRNAs that were differentially regulated across seven time points[129]. Using principal component analysis, we found that there were unique expression patterns of miRNAs in the injury phase versus the repair and fibrotic phases.…”

Section: Mirnas In Kidney Injury and Repairmentioning

confidence: 99%

MicroRNAs in injury and repair

Gerlach

Vaidya

2017

Arch Toxicol

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Organ damage and resulting pathologies often involve multiple deregulated pathways. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate a multitude of genes at the post-transcriptional level. Since their discovery over two decades ago, miRNAs have been established as key players in the molecular mechanisms of mammalian biology including the maintenance of normal homeostasis and the regulation of disease pathogenesis. In recent years, there has been substantial progress in innovative techniques to measure miRNAs along with advances in targeted delivery of agents modulating their expression. This has expanded the scope of miRNAs from being important mediators of cell signaling to becoming viable quantitative biomarkers and therapeutic targets. Currently, miRNA therapeutics are in clinical trials for multiple disease areas and vast numbers of patents have been filed for miRNAs involved in various pathological states. In this review, we summarize miRNAs involved in organ injury and repair, specifically with regards to organs that are the most susceptible to injury: the liver, heart and kidney. In addition, we review the current state of knowledge on miRNA biology, miRNA biomarkers and nucleotide-based therapeutics designed to target miRNAs to prevent organ injury and promote repair.

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Application of small RNA sequencing to identify microRNAs in acute kidney injury and fibrosis

Cited by 51 publications

References 31 publications

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury

Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex

MicroRNAs in injury and repair

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