Biochemical and Biophysical Research Communications
Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury
Section snippets
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
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Cited by (43)
Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents
2023, European Journal of Medicinal ChemistryCitation Excerpt :PDK1 plays critical roles in the regulation of the cellular processes including proliferation, apoptosis and differentiation through phosphorylation of downstream protein kinase B (Akt) [11–13]. Numbers of studies proved that knockout/inhibition of ASK1 or PDK1 alone would be beneficial to protect against inflammation and fibrosis [14–17]. However, reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation has also been discovered [18,19], which suggests the potential benefit of combination of both ASK1 and PDK1 inhibitors [20].
PIM1 attenuates renal ischemia–reperfusion injury by inhibiting ASK1-JNK/P38
2023, International ImmunopharmacologyCitation Excerpt :ASK1 is a widely studied molecule in MAP3K, which can be activated by various stress responses and induce cell death [46]. Studies have shown that ASK1-MAPK pathway is involved in the regulation of IRI in various organs including kidney, heart and liver, and arrest of ASK1 can significantly attenuate IRI [47–49]. Ser83 of ASK1 is fully phosphorylated under normal conditions which maintains its inactivation, whereas upon stress induction, Ser83 of ASK1 becomes dephosphorylated which may cause increasing autophosphorylation at Thr845 simultaneously and activates ASK1 [27,28].
Pentoxifylline treatment alleviates kidney ischemia/reperfusion injury: Novel involvement of galectin-3 and ASK-1/JNK & ERK1/2/NF-κB/HMGB-1 trajectories
2021, Journal of Pharmacological SciencesCitation Excerpt :This verity was recently highlighted in a H2O2-induced hepatotoxicity model.63 This MAP3K is introduced as a potent therapeutic target for kidney disease,64 where both ASK-1 inhibitor65 and ASK-1 knocked mice66 offered protection against renal I/R paradigm. This fact offers one mechanism for the renotherapeutic effect of PTX.
Discovery and development of ASK1 inhibitors
2020, Progress in Medicinal ChemistryRational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors
2018, European Journal of Medicinal ChemistryCitation Excerpt :A number of studies using ASK1-deficient mice suggest that ASK1 has important functions in oxidative stress-related diseases. ASK1−/− mice display a protective phenotype in multiple disease models including asthma [12], acute kidney injury [13], neurodegenerative disorders [8], cardiovascular [14,15], inflammatory [16], and metabolic disorders [17]. Thus, it is thought that small molecule compounds inhibiting ASK1 could be used for the treatment of these pathologies.