Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury

Abstract Background Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI). Methods Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI. Results We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future. Conclusions Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

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miR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury

Kidney Diseases ◽

10.1159/000520140 ◽

2021 ◽

pp. 1-11

Author(s):

Yue Zhao ◽

Yue Lang ◽

Mingchao Zhang ◽

Shaoshan Liang ◽

Xiaodong Zhu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Kidney Injury ◽

Immunofluorescent Staining ◽

Luciferase Reporter ◽

Mitochondrial Fragmentation ◽

Tubular Cells ◽

Renal Tubular Cells

Background: Mitochondria are dynamic organelles whose structure are maintained by continuous fusion and fission. During acute kidney injury (AKI) progression, mitochondrial fission in renal tubular cells was elevated, characterized by mitochondrial fragmentation. It is tightly associated with mitochondrial dysfunction, which has been proven as a critical mechanism responsible for AKI. However, the initiating factor for the disruption of mitochondrial dynamics in AKI was not well understood. Objectives: To explore the molecular mechanisms of mitochondrial disorders and kidney damage. Methods: We established cisplatin-induced AKI model in C57BL/6 mice and proximal tubular cells, and detected the expression of miR-125b by qPCR. Then we delivered miR-125b antagomir after cisplatin treatment in mice via hydrodynamic-based gene transfer technique. Subsequently, we performed luciferase reporter and immunoblotting assays to prove miR-125b could directly modulate mitofusin1 (MFN1) expression. We also tested the role of miR-125b in mitochondrial and renal injury through immunofluorescent staining, qPCR, and immunoblotting assays. Results: miR-125b levels were induced in cisplatin-challenged mice and cultured tubular cells. Anti-miR-125b could effectively alleviate cisplatin-induced mitochondrial fragmentation and kidney injury both in vitro and in vivo. Furthermore, miR-125b could directly regulate MFN1, which is a key regulator of mitochondrial fusion. Our study indicated that miR-125b is upregulated during cisplatin-induced AKI. Inhibition of miR-125b may suppress mitochondrial and renal damage through upregulating MFN1. This study suggests that miR-125b could be a potential therapeutic target in AKI.

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TAK1 deficiency attenuates cisplatin-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00516.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. F209-F215 ◽

Cited By ~ 2

Author(s):

Jun Zhou ◽

Changlong An ◽

Xiaogao Jin ◽

Zhaoyong Hu ◽

Robert L. Safirstein ◽

...

Keyword(s):

Acute Kidney Injury ◽

Proximal Tubule ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Tubular Epithelial Cell ◽

Tubular Damage ◽

Wild Type ◽

Deficient Mice

Cisplatin can cause acute kidney injury (AKI), but the molecular mechanisms are not well understood. The objective of the present study was to examine the role of transforming growth factor-β-activated kinase-1 (TAK1) in the pathogenesis of cisplatin-induced AKI. Wild-type mice and proximal tubule TAK1-deficient mice were treated with vehicle or cisplatin. Compared with wild-type control mice, proximal tubule TAK1-deficient mice had less severe kidney dysfunction, tubular damage, and apoptosis after cisplatin–induced AKI. Furthermore, conditional disruption of TAK1 in proximal tubular epithelial cells reduced caspase-3 activation, proinflammatory molecule expression, and JNK phosphorylation in the kidney in cisplatin-induced AKI. Taken together, cisplatin activates TAK1-JNK signaling pathway to promote tubular epithelial cell apoptosis and inflammation in cisplatin-induced AKI. Targeting TAK1 could be a novel therapeutic strategy against cisplatin-induced AKI.

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Cellular senescence, a novel therapeutic target for mesenchymal stem cells in acute kidney injury

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16163 ◽

2020 ◽

Author(s):

Lingfei Zhao ◽

Chenxia Hu ◽

Fei Han ◽

Dajin Chen ◽

Yanhong Ma ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Therapeutic Target ◽

Kidney Injury ◽

Novel Therapeutic

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Remote Ischemic Preconditioning Protects Cisplatin-Induced Acute Kidney Injury through the PTEN/AKT Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7629396 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Wanfen Zhang ◽

Cheng Chen ◽

Ran Jing ◽

Tongqiang Liu ◽

Bicheng Liu

Keyword(s):

Acute Kidney Injury ◽

Ischemic Preconditioning ◽

Therapeutic Strategy ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Akt Signaling ◽

Remote Ischemic Preconditioning ◽

Pten Mrna ◽

Induce Resistance ◽

In Cis

Although cisplatin (Cis) is an effective chemotherapeutic agent in treatment of various cancers, its adverse effect of nephrotoxicity limits the clinical application. Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury by applying transient, brief episodes of ischemia. However, whether RIPC exerts protective effect on Cis-induced renal injury remains unclear. In this study, we showed that RIPC significantly alleviated the renal functional and histopathological damage of Cis-induced acute kidney injury (AKI) mice. Furthermore, RIPC substantially reversed the downregulation of miR-144 and upregulation of PTEN in renal tissues of Cis-induced AKI mice and alleviated tubular cell apoptosis via activating PTEN/AKT signaling. In mechanism, we demonstrated that miR-144 directly targets the 3’-UTR of PTEN mRNA, and then the elevation of miR-144 in RIPC activates PTEN/AKT signaling by downregulating PTEN expression to achieve its antiapoptosis effect. Collectively, our results indicate that RIPC may be a potential therapeutic strategy in Cis-induced AKI, and provide insights on the underlying molecular mechanisms of cisplatin’s nephrotoxicity.

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Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705615114 ◽

2017 ◽

Vol 114 (47) ◽

pp. 12608-12613 ◽

Cited By ~ 20

Author(s):

Bing-Qing Deng ◽

Ying Luo ◽

Xin Kang ◽

Chang-Bin Li ◽

Christophe Morisseau ◽

...

Keyword(s):

Acute Kidney Injury ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Therapeutic Strategies ◽

Epoxyeicosatrienoic Acid ◽

Renal Tubular

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3β phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3β phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3β phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

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87: Retroperitoneal Fibrosis Causing Acute Kidney Injury: Current Therapeutic Approaches

American Journal of Kidney Diseases ◽

10.1053/j.ajkd.2009.01.108 ◽

2009 ◽

Vol 53 (4) ◽

pp. B44

Keyword(s):

Acute Kidney Injury ◽

Retroperitoneal Fibrosis ◽

Kidney Injury ◽

Therapeutic Approaches

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Developing better mouse models to study cisplatin-induced kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00285.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. F835-F841 ◽

Cited By ~ 36

Author(s):

Cierra N. Sharp ◽

Leah J. Siskind

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Kidney Injury ◽

Therapeutic Interventions ◽

Low Doses ◽

Dosing Regimen ◽

Risk Of Mortality ◽

Increased Risk ◽

Novel Therapeutic

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury.

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