Characterization of a Murine Model System to Study MicroRNA-147 During Inflammatory Organ Injury

Kim, Boyun; Guaregua, Victor; Chen, Xuebo; Zhao, Chad; Yeow, Wanyi; Berg, Nathaniel K.; Eltzschig, Holger K.; Yuan, Xiaoyi

doi:10.1007/s10753-021-01427-w

Cited by 7 publications

(5 citation statements)

References 118 publications

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“…Hepatic ischemia and reperfusion injury occurs during major liver surgery, or during liver transplantation, and represents a major hurdle towards improving outcomes in these clinical scenarios (Ju et al, 2016;Lee et al, 2020a;Cata et al, 2020;Conrad and Eltzschig, 2020). Previous studies had implicated hypoxia-signaling in liver protection, and provided a strong rationale for exploring the netrin-Adora2b link during hepatic ischemia and reperfusion injury (Eltzschig et al, 2009b;Gao et al, 2020;Ibars et al, 2020;Wang et al, 2021a;Ju et al, 2021;Kim et al, 2021). In this context it is not surprising that studies in mice with partial netrin-1 deletion (Ntn1 +/− ) experienced lower efficacy in reducing neutrophil infiltration, had lower levels of pro-inflammatory cytokines, and exhibited attenuated liver injury during hepatic ischemia/reperfusion injury compared to wildtype control animals (Schlegel et al, 2016).…”

Section: Hepatic Ischemia and Reperfusionmentioning

confidence: 99%

Alternative adenosine Receptor activation: The netrin-Adora2b link

et al. 2022

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During hypoxia or inflammation, extracellular adenosine levels are elevated. Studies using pharmacologic approaches or genetic animal models pertinent to extracellular adenosine signaling implicate this pathway in attenuating hypoxia-associated inflammation. There are four distinct adenosine receptors. Of these, it is not surprising that the Adora2b adenosine receptor functions as an endogenous feedback loop to control hypoxia-associated inflammation. First, Adora2b activation requires higher adenosine concentrations compared to other adenosine receptors, similar to those achieved during hypoxic inflammation. Second, Adora2b is transcriptionally induced during hypoxia or inflammation by hypoxia-inducible transcription factor HIF1A. Studies seeking an alternative adenosine receptor activation mechanism have linked netrin-1 with Adora2b. Netrin-1 was originally discovered as a neuronal guidance molecule but also functions as an immune-modulatory signaling molecule. Similar to Adora2b, netrin-1 is induced by HIF1A, and has been shown to enhance Adora2b signaling. Studies of acute respiratory distress syndrome (ARDS), intestinal inflammation, myocardial or hepatic ischemia and reperfusion implicate the netrin-Adora2b link in tissue protection. In this review, we will discuss the potential molecular linkage between netrin-1 and Adora2b, and explore studies demonstrating interactions between netrin-1 and Adora2b in attenuating tissue inflammation.

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Section: Hepatic Ischemia and Reperfusionmentioning

confidence: 99%

Alternative adenosine Receptor activation: The netrin-Adora2b link

et al. 2022

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“…Kim et al developed a transgenic mouse model of systemic inflammation and found miR-147 downregulation in brain compared to other organs (i.e., lung, kidney and stomach) and to controls [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review

Maiese

Scatena

Costantino

et al. 2022

IJMS

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Sepsis is a critical condition characterized by increased levels of pro-inflammatory cytokines and proliferating cells such as neutrophils and macrophages in response to microbial pathogens. Such processes lead to an abnormal inflammatory response and multi-organ failure. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function of gene regulation. This means that miRNAs are involved in multiple intracellular pathways and thus contribute to or inhibit inflammation. As a result, their variable expression in different tissues and organs may play a key role in regulating the pathophysiological events of sepsis. Thanks to this property, miRNAs may serve as potential diagnostic and prognostic biomarkers in such life-threatening events. In this narrative review, we collect the results of recent studies on the expression of miRNAs in heart, blood, lung, liver, brain, and kidney during sepsis and the molecular processes in which they are involved. In reviewing the literature, we find at least 122 miRNAs and signaling pathways involved in sepsis-related organ dysfunction. This may help clinicians to detect, prevent, and treat sepsis-related organ failures early, although further studies are needed to deepen the knowledge of their potential contribution.

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“…Notably, miR-147 was upregulated in human renal grafts with DGF and in cultured kidney proximal tubular cells after ATP depletion injury. Upregulation of miR-147 was detected in X-linked hereditary nephropathy, 53 3-chloro-1, 2-propanediol–induced AKI, 54 and sepsis-induced renal injury, 55 but the role and regulation of miR-147 in renal pathophysiology have not been investigated. In this study, anti–miR-147 protected against CST injury in mice and renal tubular cells in vitro .…”

Section: Discussionmentioning

confidence: 99%

miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation

Zhu

Xiang

et al. 2023

JASN

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Background Kidney injury due to cold storage–associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. Methods The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti–microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR-147 in CST injury in mouse and renal tubular cell models. Results Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti–miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro. Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147–induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. Conclusions microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.

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Characterization of a Murine Model System to Study MicroRNA-147 During Inflammatory Organ Injury

Cited by 7 publications

References 118 publications

Alternative adenosine Receptor activation: The netrin-Adora2b link

Alternative adenosine Receptor activation: The netrin-Adora2b link

Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review

miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation

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