Cellular and Molecular Predictors of Chronic Renal Dysfunction After Initial Ischemia/Reperfusion Injury of a Single Kidney1

Azuma, Haruhito; Nadeau, Kari; Takada, Moriatsu; Mackenzie, Harald S.; Tilney, Nicholas L.

doi:10.1097/00007890-199707270-00002

Cited by 204 publications

(116 citation statements)

References 18 publications

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“…2 I/R injury will not only cause undesirable organ loss in the early postoperative phase, but also compromise the outcome of long-term survival of the transplant. 27 Here, we show that transduction of a newly generated HO-1 protein with potential for clinical application can prolong cold preservation of an organ and protect it from I/R injury after transplantation.…”

Section: Discussionmentioning

confidence: 81%

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Ma¹,

Lau

Obed³

et al. 2008

Gene Ther

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Ischemia/reperfusion (I/R) injury is an unavoidable barrier that significantly affects outcome of solid organ transplantation. Here, we establish a protein transduction system to extend graft preservation time and to prevent I/R injury in heart transplantation. We generated a recombinant heme oxygenase-1 (HO-1) protein containing a modified protein transduction domain (PTD). PTD could cross cover cell membrane and carry target molecule to parenchymal cells of cold-preserved heart grafts. The newly generated PTD-HO-1 protein localized mainly in subcellular membrane organelle and nucleus after delivery that significantly prolonged cold preservation of heart grafts. This effect was associated with significantly less endothelial cell activation, less neutrophil and macrophage infiltration in PTD-HO-1-transduced heart grafts after reperfusion as compared with controls. In addition, transduction of PTD-HO-1 protein to heart graft significantly suppressed the I/R injury-associated myocardiocyte apoptosis. The infarct areas of heart graft after I/R injury were significantly reduced after PTD-HO-1 protein treatment. We show here for the first time that PTD can maintain its biological activities during cold preservation. Transduction of cell penetrating HO-1 protein significantly prolongs the cold preservation time and protects the graft from the I/R injury. This approach represents a novel method for the improvement of the overall outcome of organ transplantation.

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Section: Discussionmentioning

confidence: 81%

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Ma¹,

Lau

Obed³

et al. 2008

Gene Ther

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“…Regeneration and remodeling of the kidney results in recovery of renal function and morphology by tubular epithelial cell replacement (2,3). However, tubulointerstitial remodeling, as a result of an uncontrolled balance between synthesis and degradation of extracellular matrix (ECM) proteins, also can result in tubulointerstitial fibrosis (4,5), which is an important risk factor for progressive renal function loss (6).…”

mentioning

confidence: 99%

Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats

Broekema¹,

Harmsen²,

Luyn³

et al. 2007

Journal of the American Society of Nephrology

158

130

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Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial ␣-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-␤ and decreased transcription of bone morphogenic protein-7. TGF-␤ protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.

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“…In addition to complement, other types of stress may injure GEC. For example, during or after renal ischemia-reperfusion injury there is up-regulation of glomerular heat shock and ER stress proteins, activation of nitric-oxide synthases, glomerular infiltration with leukocytes, and development of sclerosis (23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

Role of the Endoplasmic Reticulum Unfolded Protein Response in Glomerular Epithelial Cell Injury

Cybulsky¹,

Takano²,

Papillon

et al. 2005

Journal of Biological Chemistry

104

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C5b-9-induced glomerular epithelial cell (GEC) injury in vivo (in passive Heymann nephritis) and in culture is associated with damage to the endoplasmic reticulum (ER) and increased expression of ER stress proteins. Induction of ER stress proteins is enhanced via cytosolic phospholipase A 2 (cPLA 2 ) and limits complement-dependent cytotoxicity. The present study addresses another aspect of the ER unfolded protein response, i.e. activation of protein kinase R-like ER kinase (PERK or pancreatic ER kinase), which phosphorylates eukaryotic translation initiation factor 2-␣ (eIF2␣), thereby generally suppressing translation and decreasing the protein load on a damaged ER. Phosphorylation of eIF2␣ was enhanced significantly in glomeruli of proteinuric rats with passive Heymann nephritis, compared with control. In cultured GECs, complement induced phosphorylation of eIF2␣ and reduced protein synthesis, and complement-stimulated phosphorylation of eIF2␣ was enhanced by overexpression of cPLA 2 . Ischemia-reperfusion in vitro (deoxyglucose plus antimycin A followed by glucose re-exposure) also stimulated eIF2␣ phosphorylation and reduced protein synthesis. Complement and ischemia-reperfusion induced phosphorylation of PERK (which correlates with activation), and fibroblasts from PERK knock-out mice were more susceptible to complement-and ischemia-reperfusion-mediated cytotoxicity, as compared with wild type fibroblasts. The GEC protein, nephrin, plays a key role in maintaining glomerular permselectivity. In contrast to a general reduction in protein synthesis, translation regulated by the 5-end of mouse nephrin mRNA during ER stress was paradoxically maintained, probably due to the presence of short open reading frames in this mRNA segment. Thus, phosphorylation of eIF2␣ and consequent general reduction in protein synthesis may be a novel mechanism for limiting complement-or ischemiareperfusion-dependent GEC injury.

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Cellular and Molecular Predictors of Chronic Renal Dysfunction After Initial Ischemia/Reperfusion Injury of a Single Kidney1

Cited by 204 publications

References 18 publications

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats

Role of the Endoplasmic Reticulum Unfolded Protein Response in Glomerular Epithelial Cell Injury

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