Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury

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Abstract

We investigated the role of apoptosis signal-regulating kinase 1 (ASK1) in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Blood urea nitrogen (BUN) and serum creatinine were significantly higher in ASK1+/+ mice than in ASK1−/− mice after I/R injury. Renal histology of ASK1+/+ mice showed significantly greater tubular necrosis and degradation. In ASK1−/− mice, phosphorylation of ASK1, JNK, and p38K, and the number of TUNEL-positive cells and infiltrated leukocytes decreased after I/R injury. Apoptotic changes were significantly decreased in cultured renal tubular epithelial cells (TECs) from ASK1−/− mice under hypoxic condition. Transfection with dominant-active ASK1 induced apoptosis in TECs. Protein expression of monocyte chemoattractant protein-1 (MCP-1) was significantly weaker in ASK1−/− mice after I/R injury. Transfection with dominant negative-ASK1 significantly decreased MCP-1 production in TECs. These results demonstrated that ASK1 is activated in I/R-induced AKI, and blockage of ASK1 attenuates renal tubular apoptosis, MCP-1 expression, and renal function.

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Materials and methods

Animals and ischemia/reperfusion of the kidneys. Experiments were performed on 8- to 10-week-old male C57BL/6 or ASK1−/− mice weighing 20–25 g [6]. The same background male mice (C57BL/6) obtained from Jackson Laboratories (Yokohama, Japan) served as the wild-type controls. In the I/R models, bilateral renal pedicles were clamped with surgical clips for 25 min and then released. Sham-operated mice served as the control. The animals were sacrificed at different time intervals, and the tissue and

Blood urea nitrogen, serum creatinine, histology, and leukocyte infiltration in the kidney after I/R injury in ASK1+/+ and ASK1−/− mice

ASK1−/− mice were born at the expected Mendelian frequency and were indistinguishable in appearance from the age-matched wild-type controls [6]. There were no significant differences in the body weight, basal BUN and serum creatinine levels, and renal morphology between these two groups. Bilateral renal I/R injury caused renal dysfunction in ASK1+/+ mice, as illustrated by the increase in BUN from 18.6 ± 0.7 mg/dL before I/R injury to 95.6 ± 21.8 mg/dL 24 h after it (Fig. 1A). Deficiency of ASK1

Discussion

In this study, we first demonstrated that the ASK1 pathway is activated in I/R-induced renal injury, and inhibition of the ASK1 pathway attenuates renal tubular apoptosis after I/R injury. It is well known that ischemia generates reactive oxygen species (ROS). Furthermore, previous works have shown that ROS induces ASK1 activation [14]. Therefore, ASK1 activation in renal I/R injury might be mediated by I/R-generated ROS. Previous data showed that ASK1 activates SEK1-JNK and MKK3/MKK6-p38K

References (18)

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