3-deazaneplanocin A protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

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p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00072.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. F1311-F1317 ◽

Cited By ~ 4

Author(s):

Huan Yang ◽

Ruizhao Li ◽

Li Zhang ◽

Shu Zhang ◽

Wei Dong ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Cell Apoptosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Cyclophilin D ◽

Mptp Opening ◽

Renal Tubular

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

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NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury

AJP Renal Physiology ◽

10.1152/ajprenal.00360.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. F382-F395 ◽

Cited By ~ 6

Author(s):

Dan Xu ◽

Panpan Chen ◽

Bao Wang ◽

Yanzhe Wang ◽

Naijun Miao ◽

...

Keyword(s):

Renal Injury ◽

Cell Apoptosis ◽

Cell Injury ◽

Kidney Injury ◽

Underlying Mechanism ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Common Symptom ◽

Renal Tubules ◽

Renal Tubular

Proteinuria, the most common symptom of renal injury, is an independent factor for renal tubular injury. However, the underlying mechanism remains to be fully elucidated. Mitochondrion is an important target for proteinuria-induced renal tubular cell injury. Insufficient mitophagy exacerbates cell injury by initiating mitochondrial dysfunction-related cell apoptosis. In the experiment, the role of NIP3-like protein X (NIX)-mediated mitophagy was investigated in proteinuria-induced renal injury. In this study, we demonstrated that NIX expression was reduced in renal tubules and correlated with the decline of estimated glomerular filtration rate and increase of the proteinuria in patients. In proteinuric mice, NIX-mediated mitophagy was significantly suppressed. Meanwhile, the proteinuric mice exhibited renal dysfunction, increased mitochondrial fragmentation, and tubular cell apoptosis. Overexpression of NIX attenuated those disruptions in proteinuric mice. In cultured renal tubular epithelial cells, albumin induced a decrease in NIX-mediated mitophagy and an increase in cell apoptosis. Overexpression of NIX attenuated albumin-induced cell apoptosis, whereas NIX siRNA aggravated these perturbations. These results indicate that proteinuria suppresses NIX-mediated mitophagy in the renal tubular epithelial cell, which triggers the cell undergoing mitochondria-dependent cell apoptosis. Collectively, our finding suggests that restoration of NIX-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury.

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Renal tubular cell spliced X-box binding protein 1 (Xbp1s) has a unique role in sepsis-induced acute kidney injury and inflammation

Kidney International ◽

10.1016/j.kint.2019.06.023 ◽

2019 ◽

Vol 96 (6) ◽

pp. 1359-1373 ◽

Cited By ~ 4

Author(s):

Silvia Ferrè ◽

Yingfeng Deng ◽

Sarah C. Huen ◽

Christopher Y. Lu ◽

Philipp E. Scherer ◽

...

Keyword(s):

Acute Kidney Injury ◽

Binding Protein ◽

Kidney Injury ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Unique Role ◽

Renal Tubular

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EGFR activity is required for renal tubular cell dedifferentiation and proliferation in a murine model of folic acid-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00553.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. F356-F366 ◽

Cited By ~ 39

Author(s):

Song He ◽

Na Liu ◽

George Bayliss ◽

Shougang Zhuang

Keyword(s):

Acute Kidney Injury ◽

Folic Acid ◽

Kidney Injury ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Wild Type ◽

Cell Dedifferentiation ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Proliferation of dedifferentiated intrinsic renal tubular cells has been recognized to be the major cellular event that contributes to renal repair after acute kidney injury (AKI). However, the underlying mechanism that initiates renal tubular dedifferentiation in vivo remains unexplored. Here we investigated whether epidermal growth factor receptor (EGFR) mediates this process in a murine model of folic acid (FA)-induced AKI using waved-2 mice that have reduced tyrosine kinase activity of EGFR and gefitinib, a specific EGFR inhibitor. Administration of FA for 48 h induced EGFR phosphorylation in the kidney of wild-type mice, but this was inhibited in waved-2 mice and wild-type mice given gefitinib. Compared with wild-type mice, waved-2 mice and wild-type mice treated with gefitinib had increased renal dysfunction, histologic damage, and tubular cell apoptosis after FA administration. PAX2, a dedifferentiation marker, and proliferating cell nuclear antigen, a proliferating marker, were highly expressed in renal tubular cells in wild-type mice; however, their expression was largely inhibited in the kidney of waved-2 mice. Inhibition of EGFR with gefitinib also blocked FA-induced expression of these two proteins in wild-type mice. Moreover, FA exposure resulted in phosphorylation of AKT, a downstream signaling molecule of the phosphatidylinositol 3-kinases pathway associated with renal epithelial proliferation in wild-type mice, and its phosphorylation was totally suppressed in waved-2 mice and wild-type mice given gefitinib. Taken together, these results suggest that EGFR activation is essential for initiation of renal tubular cell dedifferentiation and proliferation after AKI.

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Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury

Critical Care Medicine ◽

10.1097/ccm.0000000000002937 ◽

2018 ◽

Vol 46 (4) ◽

pp. e318-e325 ◽

Cited By ~ 23

Author(s):

Nishkantha Arulkumaran ◽

Sean Pollen ◽

Elisabetta Greco ◽

Holly Courtneidge ◽

Andrew M. Hall ◽

...

Keyword(s):

Acute Kidney Injury ◽

Mitochondrial Dysfunction ◽

Oxygen Delivery ◽

Kidney Injury ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Septic Acute Kidney Injury ◽

Renal Tubular ◽

Renal Oxygen

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AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

Scientific Reports ◽

10.1038/s41598-019-55550-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Yongjun Zhu ◽

Hongwang Cui ◽

Jie Lv ◽

Haiqin Liang ◽

Yanping Zheng ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Critical Role ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Tubular Cell ◽

Tubular Damage ◽

Renal Tubular Cell ◽

Ang Ii ◽

Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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