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A Quantitative Detection Method for MicroRNAs in the Kidney of an Ischemic Kidney Injury Mouse Model
Published on: September 11, 2020
MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action
Lucile Amrouche1,2,3, Geoffroy Desbuissons1, Marion Rabant2,4
1Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151, Paris, France.
Abstract:
AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a-/- mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a-/- mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.
Insights
MicroRNA-146a (miR-146a) plays a crucial role in kidney injury repair. Loss of miR-146a exacerbates acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) by promoting inflammation and fibrosis.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Acute kidney injury (AKI) involves tubular damage and inflammation, potentially leading to fibrosis.
- MicroRNAs (miRNAs) are implicated in regulating tissue repair processes.
- The specific role of microRNA-146a (miR-146a) in renal injury response requires elucidation.
Purpose of the Study:
- To investigate the role of miR-146a in the renal tubular response to ischemia-reperfusion injury (IRI).
- To determine the mechanisms by which miR-146a influences inflammation and fibrosis following AKI.
Main Methods:
- In vitro studies using cultured renal proximal tubular cells under proinflammatory conditions.
- In vivo studies involving unilateral IRI in wild-type and miR-146a knockout mice.
- Analysis of miR-146a expression in human kidney allografts and urine post-transplant.
- Assessment of inflammatory markers (CXCL8/CXCL1) and fibrotic markers.
Main Results:
- miR-146a expression is upregulated in response to proinflammatory stimuli and IRI in kidneys and urine.
- miR-146a knockout mice showed exacerbated tubular injury, inflammation, and fibrosis after IRI.
- miR-146a regulates IL-1 receptor-associated kinase 1 and CXCL8/CXCL1 expression.
- Inhibition of CXCL8/CXCL1 signaling ameliorated inflammation and fibrosis in miR-146a deficient mice.
Conclusions:
- miR-146a is a critical mediator in the renal tubular response to IRI.
- miR-146a acts by modulating inflammatory pathways, thereby limiting AKI and subsequent CKD development.
- Targeting miR-146a or its downstream effectors may offer therapeutic strategies for kidney disease.
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