Abstract
Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor κB (NF-κB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2α during the reperfusion period, while expression of CK2β remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2α inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2α inhibition were observed for emodin. Renoprotective effects of CK2α inhibition were associated with suppression of NF-κB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2α mediates proapoptotic and proinflammatory signaling, thus the CK2α inhibitor may be used to prevent renal I/R injuries observed in clinical settings.
Highlights
Antioxidants and anti-apoptotic therapy have been shown to be protective against ischemia reperfusion (I/R)-mediated oxidative damage in different experimental models[8,9,10,11]
To induce I/R injury, the renal pedicles were bilaterally clamped for 25 min, after which they were reperfused for various time periods (Fig. 1A)
We demonstrated for the first time that pretreatment with a double dose of CK2α inhibitor TBBt significantly protected against renal I/R injury
Summary
Antioxidants and anti-apoptotic therapy have been shown to be protective against I/R-mediated oxidative damage in different experimental models[8,9,10,11]. CK2 is upregulated in a variety of human cancers and creates a cellular environment favorable to neoplasia by enhancing cell proliferation and by inhibiting apoptosis[13,14]. In addition to its apoptotic inhibiting functions, a number of studies have suggested a pro-inflammatory role for CK2. Treatment of human Jurkat cells with TBBt leads to induction of apoptosis[22]. Another CK2 inhibitor emodin, in comparison with TBBt, is more water soluble and has a limited selectivity for CK2. Based on conflicting evidence of apoptotic induction and anti-inflammation of CK2 inhibition, we assessed the effects of TBBt on the intrinsic response to renal I/R injury
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