scholarly journals miR-21 in ischemia/reperfusion injury: a double-edged sword?

2014 ◽  
Vol 46 (21) ◽  
pp. 789-797 ◽  
Author(s):  
Xialian Xu ◽  
Alison J. Kriegel ◽  
Xiaoyan Jiao ◽  
Hong Liu ◽  
Xiaowen Bai ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Renal Interstitial Fibrosis ◽  
Rna Molecules ◽  
Programmed Cell Death 4 ◽  
Proapoptotic Gene

MicroRNAs (miRNAs or miRs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the proapoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury; however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.

scholarly journals Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis

2019 ◽  
Vol 317 (5) ◽  
pp. F1383-F1397 ◽  
Author(s):  
Anna Menshikh ◽  
Lauren Scarfe ◽  
Rachel Delgado ◽  
Charlene Finney ◽  
Yuantee Zhu ◽  
...  
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Capillary Density ◽  
Repeat Dose ◽  
Peritubular Capillary ◽  
Ckd Progression ◽  
Capillary Rarefaction

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.

Abstract 415: Asporin Contributes to Reactive Interstitial Cardiac Fibrosis by Regulating Cardiac Fibroblast Activation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Lejla Medzikovic ◽  
Laila Aryan ◽  
Gregoire Ruffenach ◽  
Mansoureh Eghbali
Keyword(s):  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Bioinformatic Analysis ◽  
Gene Signature ◽  
Cardiac Fibroblast ◽  
Collagen Production

Cardiac fibrosis critically contributes to heart failure progression. Depending on the pathological insult, cardiac fibrosis either replaces necrotic cardiomyocytes or is reactive to cardiac fibroblast (CF) activation. The extracellular matrix (ECM) consists of various proteins and the role of fibrillar collagen has been well studied. However, the role of non-fibrillar ECM proteins in cardiac fibrosis is less clear. To explore the role of ECM in reactive cardiac fibrosis, we performed bioinformatic analysis on online available microarray GEO datasets from hearts of human hypertrophic cardiomyopathy patients and two mouse models of transverse aortic constriction and Angiotensin II (AngII) infusion. We found that 27 differentially expressed genes were common between the three datasets. Among these genes was the small leucine-rich proteoglycan Asporin (ASPN). ASPN was previously shown to be upregulated in the ECM of replacement fibrosis in porcine ischemia/reperfusion injury. However, not much is known about the role of ASPN in reactive interstitial fibrosis. We show that cardiac ASPN expression is enhanced in mice after short- and long-term AngII infusion compared to saline infusion. In resident CF isolated from adult mice, ASPN expression is upregulated by both AngII and TGF-β stimulation. Here, ASPN expression correlates with a gene signature of activated CFs including periostin ( postn ), α-smooth muscle actin ( acta2 ) and collagens I and III ( col1a1, col3a1 ), and with functional characteristics of activated CFs including proliferation, migration and collagen production. Modulating ASPN via siRNA in mouse resident CFs inhibits postn, acta2, col1a1 and col3a1 expression and total collagen production, indicating repressed CF activation upon ASPN knockdown. Taken together, ASPN may be an attractive novel target against reactive interstitial fibrosis.

scholarly journals Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 306
Author(s):  
Maxime Rossi ◽  
Kéziah Korpak ◽  
Arnaud Doerfler ◽  
Karim Zouaoui Boudjeltia
Keyword(s):  
Reperfusion Injury ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Kidney Injury ◽  
Heme Oxygenase 1

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages.

scholarly journals miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

2013 ◽  
Vol 119 (3) ◽  
pp. 621-630 ◽  
Author(s):  
Ping Jia ◽  
Jie Teng ◽  
Jianzhou Zou ◽  
Yi Fang ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Renal Ischemia ◽  
Locked Nucleic Acid ◽  
Hypoxia Inducible Factor 1Α ◽  
Renal Ischemia Reperfusion Injury

Abstract Background: MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods: Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Results: Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. Conclusions: These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.

TRANSPLANT RENAL ARTERY STENOSIS: POTENTIAL ROLE OF ISCHEMIA/REPERFUSION INJURY AND LONG-TERM OUTCOME FOLLOWING ANGIOPLASTY

1999 ◽  
Vol 161 (1) ◽  
pp. 28-32 ◽  
Author(s):  
JEAN-MICHEL HALIMI ◽  
AZMI AL-NAJJAR ◽  
MATTHIAS BUCHLER ◽  
BÉATRICE BIRMELE ◽  
FRANÇOIS TRANQUART ◽  
...  
Keyword(s):  
Renal Artery ◽  
Reperfusion Injury ◽  
Renal Artery Stenosis ◽  
Potential Role ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals SIRT1-mediated acute cardioprotection

2011 ◽  
Vol 301 (4) ◽  
pp. H1506-H1512 ◽  
Author(s):  
Sergiy M. Nadtochiy ◽  
Hongwei Yao ◽  
Michael W. McBurney ◽  
Wei Gu ◽  
Leonard Guarente ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lysine Acetylation ◽  
Short Term ◽  
Lysine Deacetylase ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Overexpression studies have revealed a role for silent information regulator of transcription 1 (SIRT1) lysine deacetylase in cardioprotection against ischemia-reperfusion injury via long-term transcriptional effects. However, short-term SIRT1-mediated lysine deacetylation, within the context of acute cardioprotection, is poorly understood. In this study, the role of SIRT1 in the acute cardioprotective paradigm of first window ischemic preconditioning (IPC) was studied using SIRT1-deficient (SIRT1+/−) and SIRT1-overexpressing (SIRT1+++) mice. In wild-type hearts, cytosolic lysine deacetylation was observed during IPC, and overacetylation was observed upon pharmacological SIRT1 inhibition. Consistent with a role for SIRT1 in IPC, SIRT1+/− hearts could not be preconditioned and exhibited increased cytosolic lysine acetylation. Furthermore, SIRT1+++ hearts were endogenously protected against ischemia-reperfusion injury and exhibited decreased cytosolic acetylation. Both of these effects in SIRT1+++ mice were reversed by pharmacological SIRT1 inhibition on an acute timescale. Several downstream targets of SIRT1 were examined, with data suggesting possible roles for endothelial nitric oxide synthase phosphorylation, NF-κB, and stimulation of autophagy. In conclusion, these data suggest that SIRT1, acting on nontranscriptional targets, is required for cardioprotection by acute IPC and that SIRT1-dependent lysine deacetylation occurs during IPC and may play a role in cardioprotective signaling.

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