Cu/Zn-Superoxide Dismutase Gene Attenuates Ischemia-Reperfusion Injury in the Rat Kidney

ABSTRACT. Evidence has accumulated for a role of toxic oxygen radicals in the pathogenesis of ischemia-reperfusion injury in the kidney. The aim of this study was to evaluate the hypothesis that reducing postischemic renal injury is possible by delivery of the gene for the antioxidant enzyme superoxide dismutase (SOD). Female Sprague-Dawley rats received intravenous injections of recombinant adenovirus (1 × 109 pfu) containing the transgenes for Escherichia coli β-galactosidase (Ad-LacZ, as control) or human Cu/Zn-SOD (Ad-SOD). Three days later, renal ischemia was produced by cross-clamping the left renal vessels for 60 min. The right kidney was removed before reperfusion and processed for the transgene. Renal SOD protein and activity in rats given Ad-SOD was 2.5-fold higher than from the animals receiving Ad-LacZ. Urinary lactate dehydrogenase concentrations were elevated by ischemia-reperfusion in the Ad-LacZ group (1403 ± 112 U/L), yet values were 50% lower in Ad-SOD-treated rats. Free radical production was elevated by ischemia-reperfusion but was significantly lower in SOD-treated animals. Importantly, on postischemic day 1, glomerular filtration rates were reduced to 0.21 ml/min per 100 g in the Ad-LacZ group, whereas values remained significantly higher (0.39) in the Ad-SOD group. Two weeks after ischemia-reperfusion, inflammation, interstitial fibrosis, tubular atrophy and tissue levels of tumor necrosis factor alpha and interleukin-1 were significantly higher in the Ad-LacZ-treated than in Ad-SOD-treated rats. In conclusion, these results indicate that SOD expression can be increased by delivery of the sod gene to the kidney by intravenous injection and that sod gene transduction minimized ischemia-reperfusion-induced acute renal failure.

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Novel Insights into the Molecular Mechanisms of Ischemia/Reperfusion Injury in Kidney Transplantation

Transplantology ◽

10.3390/transplantology2020018 ◽

2021 ◽

Vol 2 (2) ◽

pp. 191-207

Author(s):

Davide Loizzo ◽

Nicola Antonio di Meo ◽

Mattia Rocco Peluso ◽

Monica Rutigliano ◽

Matteo Matera ◽

...

Keyword(s):

Kidney Transplantation ◽

Reperfusion Injury ◽

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Graft Function ◽

Adaptive Immune Response ◽

Tubular Atrophy ◽

Pleiotropic Action

Ischemia reperfusion injury (IRI) is one of the most important mechanisms involved in delayed or reduced graft function after kidney transplantation. It is a complex pathophysiological process, followed by a pro-inflammatory response that enhances the immunogenicity of the graft and the risk of acute rejection. Many biologic processes are involved in its development, such as transcriptional reprogramming, the activation of apoptosis and cell death, endothelial dysfunction and the activation of the innate and adaptive immune response. Recent evidence has highlighted the importance of complement activation in IRI cascade, which expresses a pleiotropic action on tubular cells, on vascular cells (pericytes and endothelial cells) and on immune system cells. The effects of IRI in the long term lead to interstitial fibrosis and tubular atrophy, which contribute to chronic graft dysfunction and subsequently graft failure. Furthermore, several metabolic alterations occur upon IRI. Metabolomic analyses of IRI detected a “metabolic profile” of this process, in order to identify novel biomarkers that may potentially be useful for both early diagnosis and monitoring the therapeutic response. The aim of this review is to update the most relevant molecular mechanisms underlying IRI, and also to discuss potential therapeutic targets in future clinical practice.

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Chronic Reduction in Renal Mass in the Rat Attenuates Ischemia/Reperfusion Injury and Does Not Impair Tubular Regeneration

Journal of the American Society of Nephrology ◽

10.1681/asn.v10122551 ◽

1999 ◽

Vol 10 (12) ◽

pp. 2551-2561

Author(s):

SVEN R. VERCAUTEREN ◽

DIRK K. YSEBAERT ◽

KATHLEEN E. DE GREEF ◽

ERIK J. EYSKENS ◽

MARC E. DE BROE

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Regeneration Capacity ◽

Tubular Atrophy ◽

Lewis Rats ◽

Functional Changes ◽

Outer Stripe ◽

Morphologic Data

Abstract. It is not known whether a kidney with chronic structural and functional changes is more vulnerable to an acute renal insult, and whether its regeneration capacity after injury is altered. To study this question, Lewis rats were submitted 10 wk after 5/6 nephrectomy to an ischemic insult of 60 min (remnant kidney [RK] group). Functional and morphologic data of the RK group were compared with data obtained in 10-wk uninephrectomized (1K) and normal (2K) Lewis rats with unilateral and bilateral renal ischemia, respectively. The acute postischemic decrease in creatinine clearance was smallest in the RK group, followed by the 2K and 1K groups, respectively. At days 1 and 3, fewer proximal tubules in the outer stripe of the outer medulla of the RK and 2K groups had undergone acute tubular necrosis compared with the 1K group. The mean percentage of tubules with signs of regeneration was maximal at day 3 in the three experimental groups. At day 10, regeneration was almost complete in the three groups. The number of leukocytes (OX1+cells) present in the RK before ischemia did not increase after ischemia/reperfusion injury (377 ± 146 cells/mm2at day 0) in contrast to the 1K and 2K groups. In the latter groups, the number of leukocytes had increased gradually, reaching a maximum at day 15 (1K: 960 ± 308 cells/mm2) and day 10 (2K: 668 ± 164 cells/mm2), respectively. In conclusion, this study has shown that an RK exhibiting chronic morphologic changes of interstitial fibrosis and tubular atrophy is protected against ischemia/reperfusion injury, and that its regeneration capacity is preserved. The reperfusion injury is not followed by further accumulation of leukocytes, which were already present in the RK before ischemia.

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Dynamics of hyaluronan, CD44, and inflammatory cells in the rat kidney after ischemia/reperfusion injury

International Journal of Molecular Medicine ◽

10.3892/ijmm.18.1.83 ◽

2006 ◽

Author(s):

Anne-Emilie Declèves ◽

Nathalie Caron ◽

Denis Nonclercq ◽

Alexandre Legrand ◽

Gérard Toubeau ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Rat Kidney ◽

Ischemia Reperfusion ◽

Inflammatory Cells

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Cerebroprotective Effects of Dimeric Copper(II) Bis(o-acetoxybenzoate) on Ischemia-reperfusion Injury in Gerbils

Metal-Based Drugs ◽

10.1155/mbd.2002.253 ◽

2002 ◽

Vol 8 (5) ◽

pp. 253-256 ◽

Cited By ~ 1

Author(s):

Ling Li ◽

Zhiqiang Shen ◽

Weimin Yang ◽

Wanling Wu ◽

Weiping Liu ◽

...

Keyword(s):

Superoxide Dismutase ◽

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Lipid Peroxide ◽

Superoxide Dismutase Activity ◽

Global Cerebral Ischemia ◽

Peroxide Content ◽

Copper Aspirinate

The cerebroprotective effects of copper aspirinate [dimeric copper(II) bis(o-acetoxybenzoate)] were investigated in gerbils subjected to 10-min global cerebral ischemia followed b 60-min reperfusion. The results showed that intragastric copper aspirinate (7.5, 15.0 and 30.0 mg Kg−1 ) markedly promoted the recovery of the electroencephalogram amplitude, attenuated the increase of lipid peroxide content and the decrease of superoxide dismutase activity in the cortex during ischemia-reperfusion injury. It suggested that copper aspirinate possesses potential neuroprotective properties, the mechanism of which might be related to an increase of the activity of endogenous superoxide dismutase.

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CD47 Blockade Reduces Ischemia-Reperfusion Injury and Improves Outcomes in a Rat Kidney Transplant Model

Transplantation Journal ◽

10.1097/tp.0000000000000252 ◽

2014 ◽

Vol 98 (4) ◽

pp. 394-401 ◽

Cited By ~ 19

Author(s):

Yiing Lin ◽

Pamela T. Manning ◽

Jianluo Jia ◽

Joseph P. Gaut ◽

Zhenyu Xiao ◽

...

Keyword(s):

Reperfusion Injury ◽

Kidney Transplant ◽

Ischemia Reperfusion Injury ◽

Rat Kidney ◽

Ischemia Reperfusion ◽

Transplant Model

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Protective Effects of Superoxide Dismutase against Ischemia-Reperfusion Injury: Development and Application of a Transgenic Animal Model

Plastic & Reconstructive Surgery ◽

10.1097/00006534-200301000-00042 ◽

2003 ◽

Vol 111 (1) ◽

pp. 251-255 ◽

Cited By ~ 6

Author(s):

Matthew B. Klein ◽

Pak H. Chan ◽

James Chang

Keyword(s):

Animal Model ◽

Superoxide Dismutase ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Transgenic Animal ◽

Protective Effects ◽

Transgenic Animal Model

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Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

Circulation Research ◽

10.1161/res.119.suppl_1.428 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Joshua G Travers ◽

Fadia A Kamal ◽

Michelle L Nieman ◽

Michelle A Sargent ◽

Jeffery D Molkentin ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Reperfusion Injury ◽

G Protein ◽

Knockout Mice ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

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