CaMKII as a key regulator of contrast-induced nephropathy through mPTP opening in HK-2 cells

Zhang, Ge; Liu, Kun; Wu, Yin; Zhou, Lingyun; Wang, Jianglin; Chen, Linhua; Zuo, Shi; Zuo, Xiaoxia

doi:10.1016/j.cellsig.2020.109734

Cited by 9 publications

(11 citation statements)

References 37 publications

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“…CaMKII is a ubiquitously expressed serine/threonine kinase that plays an important role in diabetic nephropathy [ 26 ] and polycystic kidney diseases [ 5 ]. Several studies have shown that CaMKII activation is involved in cell death, including RTECs [ 4 , 7 , 27 ]. Consistent with these previous studies, we found that CaMKII activity was significantly increased in ADR-treated RTECs in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitously expressed multifunctional serine/threonine kinase that plays a critical role in cell apoptosis [ 4–6 ]. CaMKII pharmacological inhibition and genetic deletion protect against endoplasmic reticulum stress-induced cardiomyocyte apoptosis [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…CaMKII pharmacological inhibition and genetic deletion protect against endoplasmic reticulum stress-induced cardiomyocyte apoptosis [ 7 ]. Furthermore, CaMKII overexpression enhances iohexol-induced mitochondrial damage and RTEC apoptosis [ 4 ]. However, it remains unclear whether CaMKII participates in the pathogenesis of RTEC apoptosis in AKI.…”

Section: Introductionmentioning

confidence: 99%

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CaMKII may regulate renal tubular epithelial cell apoptosis through YAP/NFAT2 in acute kidney injury mice

Huang

Peng

et al. 2023

Renal Failure

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Aim Renal tubular epithelial cell (RTEC) apoptosis is important in acute kidney injury (AKI). Calcium/calmodulin-dependent protein kinase II (CaMKII) plays an important role in cell apoptosis, but its potential role in AKI remains unknown. Methods Using co-immunoprecipitation, immunofluorescence, immunohistochemistry, western blotting, flow cytometry, and cell transfection, this study aimed to verify whether CaMKII is involved in RTEC apoptosis and to explore the underlying mechanism. Results We found that CaMKII was involved in RTEC apoptosis. In adriamycin-induced AKI mice, serum creatinine levels, cell apoptosis, CaMKII activity, and nuclear factor of activated T cells 2 (NFAT2) levels increased, whereas nuclear Yes-associated protein (YAP) expression decreased; inhibition of CaMKII activity reversed these changes. Phosphorylated CaMKII could bind to phosphorylated YAP in the cytoplasm and block it from entering the nucleus, thereby failing to inhibit NFAT2-mediated cell apoptosis. Sequestrated phosphorylated YAP in the RTEC cytoplasm was finally degraded by ubiquitination. Conclusion CaMKII may regulate RTEC apoptosis through YAP/NFAT2 in AKI mice. CaMKII may be a potent molecular target for AKI treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CaMKII may regulate renal tubular epithelial cell apoptosis through YAP/NFAT2 in acute kidney injury mice

Huang

Peng

et al. 2023

Renal Failure

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“…Iohexol (75 mgI/ml) was used in HK‐2 cells to establish CIN model just as our previous study. [ 37,38 ] Meanwhile, HK‐2 cells were treated with nifedipine (15 μM; Sigma‐Aldrich), amlodipine (2.5 μM; MedChemexpress), and cilnidipine (2.5 μM; MedChemexpress) 1 h before iohexol (75 mgI/ml; Shanghai General Pharmaceutical) exposure. CaMKⅡ overexpression was achieved by CaMKⅡγ plasmid (GeneChem) transfection.…”

Section: Methodsmentioning

confidence: 99%

“…[ 36 ] Further, the CaMKⅡ signaling pathway has been found to regulate the mPTP opening, which will eventually lead to Human proximal tubular epithelial cell (HK‐2 cell) death in our previous study. [ 37 ]…”

Section: Introductionmentioning

confidence: 99%

An in vivo and in vitro model on the protective effect of cilnidipine on contrast‐induced nephropathy via regulation of apoptosis and CaMKⅡ/mPTP pathway

Liu

Zhou

et al. 2022

J Biochem & Molecular Tox

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Contrast‐induced nephropathy (CIN) is an acute kidney injury (AKI) observed after the administration of contrast media. Calcium channel blockers (CCBs) have been reported to exert a renal protective effect. This study aims to investigate the role of cilnidipine, a novel CCBs, on CIN by regulating the calcium/calmodulin‐dependent protein kinase Ⅱ(CaMKⅡ)/mitochondrial permeability transition pore (mPTP) pathway. Here, iohexol, a representative contrast media, was used to establish CIN model. KN‐93 (CaMKⅡ inhibitor) and atractyloside (mPTP opener) were administered in rats, and CaMKⅡ overexpression was used in Human proximal tubular epithelial cells. Markers of renal injury (serum creatinine, blood urea nitrogen, and urinary NAGL), hematoxylin‐eosin stain, oxidative stress (ROS, superoxide dismutase [SOD], and malondialdehyde [MDA] levels), cell death (MTT and terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labeling [TUNEL]), mitochondrial function (mPTP, mitochondrial membrane potential [MMP], and ATP) were assessed. Western blots were used to measure the expression levels of Bax/Bcl‐2, caspase‐3, CaMKⅡ/mPTP signaling pathways. Results showed that cilnidipine markedly improved kidney function, and alleviated tubular cell apoptosis, oxidative stress and mitochondrial damage induced by iohexol in vitro and in vivo. The underlying mechanism may be that cilnidipine relieved CaMKⅡ activation and mPTP opening induced by iohexol. All of these protective effects of cilnidipine were attenuated by CaMKⅡ overexpression and atractyloside (mPTP opener) pretreatment. Moreover, KN‐93 (CaMKⅡ inhibitor) treatment showed a similar renal protective effect with cilnidipine, while the protective effect of cilnidipine on kidney in CIN rats was not further suppressed by KN‐93 cotreatment. These in vitro and in vivo results point toward the fact that cilnidipine might be a novel therapeutic drug against contrast‐induced nephrotoxicity in a CaMKⅡ‐dependent manner.

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Changes of energy metabolism in failing heart and its regulation by SIRT3

et al. 2023

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CaMKII as a key regulator of contrast-induced nephropathy through mPTP opening in HK-2 cells

Cited by 9 publications

References 37 publications

CaMKII may regulate renal tubular epithelial cell apoptosis through YAP/NFAT2 in acute kidney injury mice

CaMKII may regulate renal tubular epithelial cell apoptosis through YAP/NFAT2 in acute kidney injury mice

An in vivo and in vitro model on the protective effect of cilnidipine on contrast‐induced nephropathy via regulation of apoptosis and CaMKⅡ/mPTP pathway

Changes of energy metabolism in failing heart and its regulation by SIRT3

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