scholarly journals Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1934-1942 ◽  
Author(s):  
Aparna Krishnamoorthy ◽  
Amrendra Kumar Ajay ◽  
Dana Hoffmann ◽  
Tae-Min Kim ◽  
Victoria Ramirez ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
High Sensitivity ◽  
Kidney Damage ◽  
Therapeutic Interventions ◽  
Mrna Levels ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Injury And Repair

AbstractIschemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

scholarly journals Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

2012 ◽  
Vol 303 (8) ◽  
pp. F1117-F1125 ◽  
Author(s):  
Natasha M. Rogers ◽  
Mingyi Yao ◽  
Enrico M. Novelli ◽  
Angus W. Thomson ◽  
David D. Roberts ◽  
...  
Keyword(s):  
Stress Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Therapeutic Interventions ◽  
Cell Surface Receptor ◽  
Matricellular Protein ◽  
Soluble Ligand ◽  
Surface Receptor ◽  
Renal Tubular

Ischemia-reperfusion injury (IRI) remains a significant source of early and delayed renal transplant failure. Therapeutic interventions have yet to resolve this ongoing clinical challenge although the reasons for this remain unclear. The cell surface receptor CD47 is widely expressed on vascular cells and in tissues. It has one known soluble ligand, the stress-released matricellular protein thrombospondin-1 (TSP1). The TSP1-CD47 ligand receptor axis controls a number of important cellular processes, inhibiting survival factors such as nitric oxide, cGMP, cAMP, and VEGF, while activating injurious pathways such as production of reactive oxygen species. A role of CD47 in renal IRI was recently revealed by the finding that the TSP1-CD47 axis is induced in renal tubular epithelial cells (RTEC) under hypoxia and following IRI. The absence of CD47 in knockout mice increases survival, mitigates RTEC damage, and prevents subsequent kidney failure. Conversely, therapeutic blockade of TSP1-CD47 signaling provides these same advantages to wild-type animals. Together, these findings suggest an important role for CD47 in renal IRI as a proximate promoter of injury and as a novel therapeutic target.

scholarly journals Hypoxic mesenchymal stem cells ameliorate acute kidney ischemia-reperfusion injury via enhancing renal tubular autophagy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei-Cheng Tseng ◽  
Pei-Ying Lee ◽  
Ming-Tsun Tsai ◽  
Fu-Pang Chang ◽  
Nien-Jung Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Recovery ◽  
Trophic Factors ◽  
Left Renal Artery ◽  
Renal Tubular Cells ◽  
Cell Based Therapy ◽  
Renal Tubular

Abstract Background Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. Methods Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. Result HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. Conclusion The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.

scholarly journals Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dan Wen ◽  
Yan-Fang Zou ◽  
Yao-Hui Gao ◽  
Qian Zhao ◽  
Yin-Yin Xie ◽  
...  
Keyword(s):  
Dna Binding ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Mrna Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Renal Tubular ◽  
Inhibitor Of Dna Binding

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1αduring hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1αcan regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.

scholarly journals Renal tubular arginase‐2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia‐reperfusion injury in mice

2020 ◽  
Vol 229 (3) ◽  
Author(s):  
Camille Ansermet ◽  
Gabriel Centeno ◽  
Sylviane Lagarrigue ◽  
Svetlana Nikolaeva ◽  
Hikari A. Yoshihara ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Damage ◽  
Renal Tubular

scholarly journals Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Shataakshi Dube ◽  
Tejasvi Matam ◽  
Jessica Yen ◽  
Henry E. Mang ◽  
Pierre C. Dagher ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Organ Injury ◽  
Mrna Levels ◽  
Kidney Dysfunction ◽  
Stat3 Signaling ◽  
Proximal Tubular

STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.

scholarly journals PTEN alleviates maladaptive repair of renal tubular epithelial cells by restoring CHMP2A-mediated phagosome closure

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Huizhen Wang ◽  
Yifan Wang ◽  
Xin Wang ◽  
Huimi Huang ◽  
Jingfu Bao ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Renal Fibrosis ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mass Spectrometry Analysis ◽  
Acute Injury ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

AbstractPhosphatase and Tensin Homolog on chromosome Ten (PTEN) has emerged as a key protein that governs the response to kidney injury. Notably, renal adaptive repair is important for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. To test the role of PTEN in renal repair after acute injury, we constructed a mouse model that overexpresses PTEN in renal proximal tubular cells (RPTC) by crossing PTENfl-stop-fl mice with Ggt1-Cre mice. Mass spectrometry-based proteomics was performed after subjecting these mice to ischemia/reperfusion (I/R). We found that PTEN was downregulated in renal tubular cells in mice and cultured HK-2 cells subjected to renal maladaptive repair induced by I/R. Renal expression of PTEN negatively correlated with NGAL and fibrotic markers. RPTC-specific PTEN overexpression relieved I/R-induced maladaptive repair, as indicated by alleviative tubular cell damage, apoptosis, and subsequent renal fibrosis. Mass spectrometry analysis revealed that differentially expressed proteins in RPTC-specific PTEN overexpression mice subjected to I/R were significantly enriched in phagosome, PI3K/Akt, and HIF-1 signaling pathway and found significant upregulation of CHMP2A, an autophagy-related protein. PTEN deficiency downregulated CHMP2A and inhibited phagosome closure and autolysosome formation, which aggravated cell injury and apoptosis after I/R. PTEN overexpression had the opposite effect. Notably, the beneficial effect of PTEN overexpression on autophagy flux and cell damage was abolished when CHMP2A was silenced. Collectively, our study suggests that PTEN relieved renal maladaptive repair in terms of cell damage, apoptosis, and renal fibrosis by upregulating CHMP2A-mediated phagosome closure, suggesting that PTEN/CHMP2A may serve as a novel therapeutic target for the AKI to CKD transition.

scholarly journals Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

2020 ◽  
Vol 6 (33) ◽  
pp. eaaz0748
Author(s):  
Tao-Tao Tang ◽  
Bin Wang ◽  
Min Wu ◽  
Zuo-Lin Li ◽  
Ye Feng ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Interleukin 10 ◽  
Extracellular Vesicle ◽  
M2 Macrophage ◽  
Renal Tubular ◽  
The Stability

Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)–loaded EVs (IL-10+ EVs) by engineering macrophages for treating ischemic acute kidney injury (AKI). Delivery of IL-10 via EVs enhanced not only the stability of IL-10, but also its targeting to the kidney due to the adhesive components on the EV surface. Treatment with IL-10+ EVs significantly ameliorated renal tubular injury and inflammation caused by ischemia/reperfusion injury, and potently prevented the transition to chronic kidney disease. Mechanistically, IL-10+ EVs targeted tubular epithelial cells, and suppressed mammalian target of rapamycin signaling, thereby promoting mitophagy to maintain mitochondrial fitness. Moreover, IL-10+ EVs efficiently drove M2 macrophage polarization by targeting macrophages in the tubulointerstitium. Our study demonstrates that EVs can serve as a promising delivery platform to manipulate IL-10 for the effective treatment of ischemic AKI.

scholarly journals Plasma Concentrations of Extracellular DNA in Acute Kidney Injury

Diagnostics ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 152 ◽  
Author(s):  
Jordanka Homolová ◽  
Ľubica Janovičová ◽  
Barbora Konečná ◽  
Barbora Vlková ◽  
Peter Celec ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Plasma Concentrations ◽  
Kidney Injury ◽  
High Sensitivity ◽  
Diagnostic Methods ◽  
Extracellular Dna ◽  
Potential Marker

Current diagnostic methods of acute kidney injury (AKI) have limited sensitivity and specificity. Tissue injury has been linked to an increase in the concentrations of extracellular DNA (ecDNA) in plasma. A rapid turnover of ecDNA in the circulation makes it a potential marker with high sensitivity. This study aimed to analyze the concentration of ecDNA in plasma in animal models of AKI. Three different fractions of ecDNA were measured—total ecDNA was assessed fluorometrically, while nuclear ecDNA (ncDNA) and mitochondrial DNA (mtDNA) were analyzed using quantitative real-time PCR. AKI was induced using four different murine models of AKI-bilateral ureteral obstruction (BUO), glycerol-induced AKI (GLY), ischemia–reperfusion injury (IRI) and bilateral nephrectomy (BNx). Total ecDNA was significantly higher in BUO (p < 0.05) and GLY (p < 0.05) compared to the respective control groups. ncDNA was significantly higher in BUO (p < 0.05) compared to SHAM. No significant differences in the concentrations of mtDNA were found between the groups. The plasma concentrations of different fractions of ecDNA are dependent on the mechanism of induction of AKI and warrant further investigation as potential surrogate markers of AKI.

scholarly journals HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David D. Aufhauser ◽  
Paul Hernandez ◽  
Seth J. Concors ◽  
Ciaran O’Brien ◽  
Zhonglin Wang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Tubules ◽  
Renal Protection ◽  
Renal Tubular Cells ◽  
Renal Ischemia Reperfusion Injury ◽  
Renal Tubular

AbstractHistone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

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