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A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

Gueler F, Shushakova N, Mengel M, Hueper K, Chen R, Liu X, Park JK, Haller H, Wensvoort G, Rong S - PLoS ONE (2015)

Bottom Line: The treatment resulted in markedly improved survival in a dose dependent manner.EA-230 improved both GFR and RBF significantly.Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

No MeSH data available.


Related in: MedlinePlus

Acute tubular necrosis (A-C) two days after IRI affected ∼25% of tubuli in the vehicle treated mice and was less in the EA-230 treated mice (A-C, magnification 200 fold).The number of Ki-67 positive tubular epithelial cells as marker of proliferation (red staining) was significantly higher in EA-230 treated kidneys two days after IRI (D-F, magnification 200fold, the autofluorescent kidney tissue appears green).
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pone.0115709.g002: Acute tubular necrosis (A-C) two days after IRI affected ∼25% of tubuli in the vehicle treated mice and was less in the EA-230 treated mice (A-C, magnification 200 fold).The number of Ki-67 positive tubular epithelial cells as marker of proliferation (red staining) was significantly higher in EA-230 treated kidneys two days after IRI (D-F, magnification 200fold, the autofluorescent kidney tissue appears green).

Mentions: To determine whether better survival was associated with improved renal blood flow (RBF) and renal function, PAH and inulin clearance measurements were performed. EA-230 treatment significantly increased RBF (Fig. 1C, *p<0.05). In addition, glomerular filtration rate (GFR) as measured by inulin clearance (Fig. 1D, *p<0.05) and urine output during the 90min collection period (Fig. 1E, *p<0.05) were significantly higher in EA-230 treated mice than in vehicle treated controls after IRI. Tissue damage two days after IRI was minimal in the EA-230 treated mice which had only mild acute tubular necrosis (ATN) with fewer than 10% of tubuli affected. In contrast, vehicle treated animals had moderate to severe ATN (∼25% tubular damage two days after IRI; Fig. 2 A-C, *p<0.05).


A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

Gueler F, Shushakova N, Mengel M, Hueper K, Chen R, Liu X, Park JK, Haller H, Wensvoort G, Rong S - PLoS ONE (2015)

Acute tubular necrosis (A-C) two days after IRI affected ∼25% of tubuli in the vehicle treated mice and was less in the EA-230 treated mice (A-C, magnification 200 fold).The number of Ki-67 positive tubular epithelial cells as marker of proliferation (red staining) was significantly higher in EA-230 treated kidneys two days after IRI (D-F, magnification 200fold, the autofluorescent kidney tissue appears green).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4305280&req=5

pone.0115709.g002: Acute tubular necrosis (A-C) two days after IRI affected ∼25% of tubuli in the vehicle treated mice and was less in the EA-230 treated mice (A-C, magnification 200 fold).The number of Ki-67 positive tubular epithelial cells as marker of proliferation (red staining) was significantly higher in EA-230 treated kidneys two days after IRI (D-F, magnification 200fold, the autofluorescent kidney tissue appears green).
Mentions: To determine whether better survival was associated with improved renal blood flow (RBF) and renal function, PAH and inulin clearance measurements were performed. EA-230 treatment significantly increased RBF (Fig. 1C, *p<0.05). In addition, glomerular filtration rate (GFR) as measured by inulin clearance (Fig. 1D, *p<0.05) and urine output during the 90min collection period (Fig. 1E, *p<0.05) were significantly higher in EA-230 treated mice than in vehicle treated controls after IRI. Tissue damage two days after IRI was minimal in the EA-230 treated mice which had only mild acute tubular necrosis (ATN) with fewer than 10% of tubuli affected. In contrast, vehicle treated animals had moderate to severe ATN (∼25% tubular damage two days after IRI; Fig. 2 A-C, *p<0.05).

Bottom Line: The treatment resulted in markedly improved survival in a dose dependent manner.EA-230 improved both GFR and RBF significantly.Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

No MeSH data available.


Related in: MedlinePlus