• The Korean Journal of Physiology and Pharmacology
• /
• v.6 no.3
• /
• pp.155-160
• /
• 2002

It is not known whether gender differences play a role in susceptibility to ischemic acute renal failure. Thus, we examined if there were any differences in susceptibility between male and female mice to kidney ischemic injury, and if so, whether it is due to differences in mitogen activated protein kinases (MAPKs) or inflammatory responses to ischemia. Female mice were protected against kidney ischemia when compared with males. Thirty minutes of bilateral ischemia resulted in marked functional and morphological damages in males, but not in females. The ischemia-induced phosphorylation of c-jun N-terminal stress-activated protein kinases (JNKs) was higher in males than in females. Phosphorylation of extracellular signal-regulated kinases (ERKs) was lower in males than in females. Post- ischemia medullary infiltration of RAW 264.7 cell, a monocyte-macrophage cell, and intercellular adhesion molecule-1 (ICAM-1) were greater in males than in females. In conclusion, males were much more susceptible to ischemia than females. The enhanced propensity to ischemic injury in males was correlated with greater activation of JNKs, greater expression of ICAM-1, and greater trapping of leukocytes in the medulla.

• Biomedical Science Letters
• /
• v.10 no.4
• /
• pp.341-346
• /
• 2004

Tumor necrosis factor-α (TNF-α) or its mRNA expression are increased in acute nephrosis of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-α production, provides a protective effect against hypoxia-induced cell injury in rabbit renal cortical slices. To induce hypoxia-induced cell injury, renal cortical slices were exposed to 100% N₂ atmosphere. Control slices were exposed to 100% O₂ atmosphere. The cell injury was estimated by measuring lactate dehydrogenase (LDH) release and p-aminohippurate (PAH) uptake. Exposure of slices to hypoxia increased the LDH release in a time-dependent manner. However, when slices were exposed to hypoxia in the presence of PTX, the LDH release was decreased. The protective effect of PTX was dose-dependent over the concentrations of 0.05∼1 mM. Hypoxia did not increase lipid peroxidation, whereas an organic hydroperoxide t-butylhydroperoxide (tBHP) resulted in a significant increase in lipid peroxidation. PTX did not affect tBHP-induced lipid peroxidation. Hypoxia decreased PAH uptake, which was significantly attenuated by PTX and glycine. tBHP-induced inhibition of PAH uptake was not altered by PTX, although it was prevented by antioxidant deferoxarnine. The PAH uptake by slices in rabbits with ischemic acute renal failure was prevented by PTX pretreatment. These results suggest that PTX may exert a protective effect against hypoxia-induced cell injury and its effect may due to inhibition of the TNF-α production, but not by its antioxidant action.

• Journal of Veterinary Clinics
• /
• v.25 no.4
• /
• pp.257-262
• /
• 2008

Renal ischemia-reperfusion injury is great clinical important because viability of the transplanted organ depends on the tolerance of the graft to ischemia-reperfusion injury, an inevitable processing during surgery. The purpose of this study was to investigate the effects of irrigation-aspiration in ischemia-reperfusion injury model induced by cross-clamping of renal vessels. Blood samples were collected from these dogs for measurement of kidney function and antioxidant enzyme activity, and RI at the intrarenal artery was measured at different time intervals. And the kidneys were taken for histopathologic evaluation at day 14. Kidney function (Cr and BUN) showed a significant increasing in untreated group compared to treated group. Resistive index of intrarenal artery was no significant difference among the groups. Activity of antioxidant enzymes in plasma was significant decrease in untreated group compare to control group while in treated group was no significant difference compared to control group. In histopathologic finding, treated group was showed less damage than that of untreated group. This result suggests that the processing of irrigation-aspiration is useful to reducing ischemia-reperfusion injury.

• Journal of Veterinary Clinics
• /
• v.29 no.5
• /
• pp.372-376
• /
• 2012

Acute kidney injury (AKI) is a serious problem associated with high morbidity and mortality. Ischemia-reperfusion is an important cause of acute kidney injury. This study was performed to ascertain clinically useful biomarkers for the diagnosis of AKI. In three miniature pigs, AKI were induced by 60 minutes of bilateral renal ischemia by the clamping renal artery. Blood and urine samples were collected from the pigs prior to clamping (baseline) and 0, 1, 3 and 5 days post-clamping. Serum blood urea nitrogen (BUN), creatinine, sodium and uric acid were measured in serum and urine samples. Fractional excretion of sodium ($FE_{Na}$) and fractional excretion of uric acid ($FE_{UA}$) were calculated. Also, interleukin (IL)-6, IL-18, liver type fatty acid binding protein (L-FABP) and glutathione-S-transferase (GST) were detected by Western immunoblotting. Serum BUN and creatinine levels were increased significantly at day 1 post-clamping in all three miniature pigs. However, $FE_{Na}$ and $FE_{UA}$ showed marked individual differences. Western immunoblotting revealed significantly increased levels of IL-6, IL-18, L-FABP and GST in post-ischemic urine, compared to pre-clamping. While more research concerning the variance of $FE_{Na}$ and $FE_{UA}$ is needed, serum BUN, creatinine, IL-6, IL-18, L-FABP and GST may be sensitive urine biomarkers for diagnosis of AKI together with other biomarkers in the porcine ischemia-reperfusion model.

• Journal of Veterinary Clinics
• /
• v.26 no.5
• /
• pp.441-444
• /
• 2009

Ischemia-reperfusion (I/R) injury is associated with an increased risk of acute rejection, delayed graft function and long-term changes after kidney transplantation. The reperfusion models remain unsolved complications such as vascular obstruction and blood leakage. We developed an alternative model of isolated hemoperfusion in porcine kidneys. In the present study we introduced a newly developed reperfusion method. A connector was used instead of surgical suture for the vascular anastomosis on the inguinal region in which main femoral vessels are parallel and big enough to perfuse the kidney. To assess renal perfusion quality of the modified hemoreperfusion model, we analyzed both hemodynamic values and patterns of I/R injury following a renal reperfusion. Following unilateral nephrectomy, the kidneys were preserved for 0, 24 and 48 hours at $4^{\circ}C$ with histidine-tryptophan ketogluatarate (HTK) solution and reperfused for 3 hours by vascular anastomosis connected to the femoral artery and vein in inguinal region. Histolopathological examinations were assessed on kidney biopsy specimens, taken after each cold storage and reperfusion. No differences of hemodynamic values were observed between aorta and femoral artery. The average warm ischemia time before reperfusion start was $7.0{\pm}1.1$ minutes. There were no complications including vascular obstruction and blood leakage during the reperfusion. I/R injury of the perfused kidneys in this model was dependent upon the cold ischemia time. The results support that the modified perfusion model is simple and appropriate for the study of early renal I/R injury and transplant immunology.

• Journal of Veterinary Clinics
• /
• v.24 no.2
• /
• pp.94-98
• /
• 2007

This study was to investigate the effects of ascorbic acid and alpha-tocopherol on the attenuation of renal ischemia-reperfusion (IR) injury in pigs. Ten pigs were subjected to 60 minutes of warm unilateral renal ischemia followed by removal of contralateral kidney and then divided into two groups. Treatment group was performed ascorbic acid and alpha-tocopherol pretreatment 2 days before operation and ascorbic acid with heparin-saline solution irrigation-aspiration. Otherwise, control group used only irrigation-aspiration of heparin-saline solution. Blood samples were collected from these pigs for measurement of serum blood urea nitrogen (BUN) and creatinine values, antioxidant superoxide dismutase (SOD) at pre, day 1, day 3, day 7 and day 14. The kidneys were taken for histopathologic evaluation after euthanasia on postoperative day 14. The levels of BUN were significantly increased in the control group on day 1, day 3 and day 7 (P<0.05). And the level of creatinine was significantly increased in the control group on day 3 (p<0.05). Activity of antioxidant enzymes in plasma revealed significant difference (p<0.05) between control and treatment group at day 14. In histopathologic findings, treatment group was showed less damage than that of control group on the basis of renal tubular damage. It was concluded that ascorbic acid and alpha-tocopherol attenuated renal I/R injury in the pigs.

• Journal of Medicine and Life Science
• /
• v.15 no.2
• /
• pp.37-41
• /
• 2018

Mitochondrial injury in renal tubule has been recognized as a major contributor in acute kidney injury (AKI) pathogenesis. Ischemic insult, nephrotoxin, endotoxin and contrast medium destroy mitochondrial structure and function as well as their biogenesis and dynamics, especially in renal proximal tubule, to elicit ATP depletion. Mitochondrial fatty acid ${\beta}$-oxidation (FAO) is the preferred source of ATP in the kidney, and its impairment is a critical factor in AKI pathogenesis. This review explores current knowledge of mitochondrial dysfunction and energy depletion in AKI and prospective views on developing therapeutic strategies targeting mitochondrial dysfunction in AKI.

• Journal of Veterinary Clinics
• /
• v.27 no.5
• /
• pp.553-558
• /
• 2010

The purpose of this study was to investigate the effects of premedicated ascorbic acid and hepa-saline irrigation/aspiration on attenuation of ischemia-reperfusion (I/R) injury and recovery of renal function in canine nephrotomy model. In the canine model, nine mixed dogs were subjected to renal nephrotomy with premedicated ascorbic acid and hepa-saline irrigation-aspiration (treatment group 2), and only hepa-saline irrigation-aspiration (treatment group 1). The level of renal function and antioxidant enzymes after nephrotomy were measured. And the expression pattern of TNF-${\alpha}$ and INF-${\gamma}$ was examined in the renal tissue at $7^{th}$ day after nephrotomy. BUN and creatinine levels significantly decreased in the treatment group 1 and 2 compared to that of control group at the $3^{rd}$, 5th and $7^{th}$ day after reperfusion (p < 0.05). And, there was significant difference between treatment group 1 and 2 at the $3^{rd}$ day after reperfusion (p < 0.05). The activities of antioxidant enzymes in plasma was significantly increased in the treatment group 1 and 2 compared to that of control group at the $3^{rd}$, $5^{th}$ and $7^{th}$ day after reperfusion (p < 0.05). And, there was significant difference between treatment group 1 and 2 at the $3^{rd}$ day after reperfusion (p < 0.05). TNF-${\alpha}$ was decreased and INF-${\gamma}$ was increased in treatment groups. The result of this study suggested that irrigation-aspiration has effects on attenuation of renal ischemia-reperfusion injury, and the exogenous ascorbic acid has a role in the attenuation of renal ischemia-reperfusion injury and recovery of renal function in canine nephrotomy model.

• Journal of Veterinary Clinics
• /
• v.26 no.2
• /
• pp.138-143
• /
• 2009

Ischemia/reperfusion injury(I/RI) is the major cause of acute renal failure and delayed graft function(DGF) unavoidable in renal transplantation. Enormous studies on ischemia damage playing a role in activating graft rejection factors, such as T cells or macrophages, are being reported. Present study was performed to determine whether ischemia time would play an important role in activating rejection-related factors or not in rat models of I/RI. Male Sprague-Dawley rats were submitted to 30, 45, and 60 minutes of warm renal ischemia with nephrectomy or control animals underwent sham operation(unilateral nephrectomy). Renal function and survival rates were evaluated on day 0, 1, 2, 3, 5 and 7. Immunofluorescence staining of dendritic cells(DCs), natural killer(NK) cells, macrophages, B cells, CD4+ and CD8+ T cells were measured on day 1 and 7 after renal I/RI. Survival rates dropped below 50% after day 3 in 45 minutes ischemia. Histologic analysis of ischemic kidneys revealed a significant loss of tubular architecture and infiltration of inflammatory cells. DCs, NK cells, macrophages, CD4+ and CD8+ T cells were infiltrated from a day after I/RI depending on ischemia time. Antigen presenting cells(DCs, NK cells or macrophages) and even T cells were infiltrated 24 hours post-I/RI, which is at the time of acute tubular necrosis. During the regeneration phase, not only these cells increased but B cells also appeared in more than 45 minutes ischemia. The numbers of the innate and the adaptive immune cells increased depending on ischemia as well as reperfusion time. These changes of infiltrating cells resulting from each I/RI model show that ischemic time plays a role in activating rejection related immune factors and have consequences on progression of renal disease in transplanted and native kidneys.

• Molecules and Cells
• /
• v.42 no.12
• /
• pp.893-905
• /
• 2019

Mitochondria are highly dynamic organelles that constantly undergo fission and fusion processes that closely related to their function. Disruption of mitochondrial dynamics has been demonstrated in acute kidney injury (AKI), which could eventually result in cell injury and death. Previously, we reported that augmenter of liver regeneration (ALR) alleviates renal tubular epithelial cell injury. Here, we gained further insights into whether the renoprotective roles of ALR are associated with mitochondrial dynamics. Changes in mitochondrial dynamics were examined in experimental models of renal ischemia-reperfusion (IR). In a model of hypoxia-reoxygenation (HR) injury in vitro, dynamin-related protein 1 (Drp1) and mitochondrial fission process protein 1 (MTFP1), two key proteins of mitochondrial fission, were downregulated in the Lv-ALR + HR group. ALR overexpression additionally had an impact on phosphorylation of Drp1 Ser637 during AKI. The inner membrane fusion protein, Optic Atrophy 1 (OPA1), was significantly increased whereas levels of outer membrane fusion proteins Mitofusin-1 and -2 (Mfn1, Mfn2) were not affected in the Lv-ALR + HR group, compared with the control group. Furthermore, the mTOR/4E-BP1 signaling pathway was highly activated in the Lv-ALR + HR group. ALR overexpression led to suppression of HR-induced apoptosis. Our collective findings indicate that ALR gene transfection alleviates mitochondrial injury, possibly through inhibiting fission and promoting fusion of the mitochondrial inner membrane, both of which contribute to reduction of HK-2 cell apoptosis. Additionally, fission processes are potentially mediated by promoting tubular cell survival through activating the mTOR/4E-BP1 signaling pathway.