scholarly journals The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 20 (20) ◽  
pp. 5238 ◽  
Author(s):  
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Smaranda Radu ◽  
Claudia Florida Costea ◽  
Manuela Ciocoiu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

scholarly journals Curcumin-Loaded Nanoparticles Protect Against Rhabdomyolysis-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 2143-2154 ◽  
Author(s):  
Xiaoling Chen ◽  
Jian Sun ◽  
Hailun Li ◽  
Hongwu Wang ◽  
Yongtao Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Treatment Efficacy ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubules ◽  
Drug Release Profile ◽  
Renal Tubular

Background/Aims: Rhabdomyolysis (RM) is a potentially life-threatening condition that results from the breakdown of muscle and consequent release of toxic compounds into circulation. The most common and severe complication of RM is acute kidney injury (AKI). This study aimed to evaluate the efficacy and mechanisms of action of curcumin-loaded nanoparticles (Cur-NP) for treatment of RM-induced AKI. Methods: Curcumin-NP was synthesized using the nanocarrier distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to achieve a prolonged and constant drug release profile compared with the curcumin-free group. The anti-AKI effects of Curcumin-NP were examined both in vitro (myoglobin-treated renal tubular epithelial HK-2 cells) and in vivo (glycerol-induced AKI model). Results: Our results indicated that Curcumin-NP reversed oxidative stress, growth inhibition and cell apoptosis accompanied with down-regulation of apoptotic markers Caspase-3 and GRP-78 in vitro. In vivo studies revealed enhanced AKI treatment efficacy with Curcumin-NP as characterized by reduced serum creatine phosphokinase (CPK), creatinine (Cr) and urea and less severe histological damage in renal tubules. In addition, kidney tissues from Curcumin-NP-treated AKI rats exhibited reduced oxidative stress, apoptosis, and cleaved Capase-3 and GRP-78 expression. Conclusion: Our results suggest that nanoparticle-loaded curcumin enhances treatment efficacy for RM-induced AKI both in vitro and in vivo.

scholarly journals Isoliquiritigenin attenuates LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy

2020 ◽  
Author(s):  
Yun Tang ◽  
Yanmei Wang ◽  
Chan Wang ◽  
Meidie Yu ◽  
Li Li ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Dysfunction ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Renal Tubular Cells ◽  
Septic Acute Kidney Injury ◽  
Life Threatening ◽  
Renal Tubular

Abstract Septic acute kidney injury (AKI) mainly results in life-threatening renal dysfunction involving renal tubular injury to bring heavy burden to patients in intensive care unit (ICU). However, there is still a lack of therapy to prevent septic AKI effectively and inexpensive. To observe the role and novel mechanism of isoliquiritigenin (ISL) which isolated from the roots of licorice in septic AKI, we used LPS to induce renal tubular injury upon septic AKI both in vitro and in vivo. 50mg/kg ISL and 5 mg/kg Ferrostatin-1 were once given to the male C57BL/6 mice one hour before 1 mg/kg LPS i.p injection. 50 μM and 100 μM ISL respectively pre-treat the human renal tubular cells 5 hrs before 2 μg/ml LPS stimulation. We found ISL pretreatment apparently reversed LPS-induced renal dysfunction and ameliorated murine renal tubular injury by suppression HMGB1 pathway. Furthermore, we observed that LPS induced autophagy and ferroptosis in renal tubular, whereas ISL pretreatment significantly suppress autophagy and ferroptosis of renal tubular both in vitro and in vivo. Mechanically, autophagy activated ferroptosis via NCOA4-mediated ferritinophagy. Moreover, HMGB1 is required for ferritinophagy in renal tubular. ISL treatment inhibited the expression of HMGB1. Taken together, these results suggest that ISL protects LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy.

scholarly journals AMPK-mediated activation of Akt protects renal tubular cells from stress-induced apoptosis in vitro and ameliorates ischemic AKI in vivo

2019 ◽  
Vol 317 (1) ◽  
pp. F1-F11 ◽  
Author(s):  
Wilfred Lieberthal ◽  
Meiyi Tang ◽  
Mersema Abate ◽  
Mark Lusco ◽  
Jerrold S. Levine
Keyword(s):  
Kidney Injury ◽  
Target Of Rapamycin ◽  
Akt Pathway ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Mechanistic Target Of Rapamycin ◽  
Renal Tubular ◽  
Induced Apoptosis

We have reported that preconditioning renal tubular cells (RTCs) with A-769662 [a pharmacological activator of AMP-activated protein kinase (AMPK)] reduces apoptosis of RTCs induced by subsequent stress and ameliorates the severity of ischemic acute kidney injury (AKI) in mice. In the present study, we examined the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in mediating these effects. Using shRNA, we developed knockdown (KD) RTCs to confirm that any novel effects of A-769662 are mediated specifically by AMPK. We reduced expression of the total β-domain of AMPK in KD RTCs by >80%. Control RTCs were transfected with “scrambled” shRNA. Preconditioning control RTCs with A-769662 increased both the phosphorylation (activity) of AMPK and survival of these cells when exposed to subsequent stress, but neither effect was observed in KD cells. These data demonstrate that activation of AMPK by A-769662 is profoundly impaired in KD cells. A-769662 activated PI3K and Akt in control but not KD RTCs. These data provide novel evidence that activation of the PI3K/Akt pathway by A-769662 is mediated specifically through activation of AMPK and not by a nonspecific mechanism. We also demonstrate that, in control RTCs, Akt plays a role in mediating the antiapoptotic effects of A-769662. In addition, we provide evidence that AMPK ameliorates the severity of ischemic AKI in mice and that this effect is also partially mediated by Akt. Finally, we provide evidence that AMPK activates PI3K by inhibiting mechanistic target of rapamycin complex 1 and preventing mechanistic target of rapamycin complex 1-mediated inhibition of insulin receptor substrate-1-associated activation of PI3K.

scholarly journals PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Dou ◽  
Hang Tong ◽  
Yichun Yang ◽  
Han Zhang ◽  
Hua Gan
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Induced Apoptosis

We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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

2017 ◽  
Vol 114 (47) ◽  
pp. 12608-12613 ◽  
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.

scholarly journals The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110374
Author(s):  
Hai-Peng Fan ◽  
Zhi-Xia Zhu ◽  
Jia-Jun Xu ◽  
Yu-Tang Li ◽  
Chun-Wen Guo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Susceptibility ◽  
Kidney Injury ◽  
In Vivo Model ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Downstream Target ◽  
Renal Tubular

Objective This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). Methods A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. Results CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. Conclusions CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.

Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tomoaki Nagao ◽  
Takafumi Okura ◽  
Akiko Tanino ◽  
Ken-ichi Miyoshi ◽  
Masayoshi Kukida ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Injury ◽  
Immunohistochemical Analysis ◽  
Tubular Injury ◽  
Histological Changes ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear. The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI). AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice. These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.

scholarly journals Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

2011 ◽  
Vol 301 (1) ◽  
pp. F162-F170 ◽  
Author(s):  
Qingqing Wei ◽  
William D. Hill ◽  
Yunchao Su ◽  
Shuang Huang ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Heme Oxygenase ◽  
Cell Injury ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells

Granulocyte colony-stimulating factor (G-CSF) is renoprotective during acute kidney injury (AKI) induced by ischemia and cisplatin nephrotoxicity; however, the underlying mechanism is not entirely clear. Rhabdomyolysis is another important clinical cause of AKI, due to the release of nephrotoxins (e.g., heme) from disrupted muscles. The current study has determined the effects of G-CSF on rhabdomyolysis-associated AKI using in vivo and in vitro models. In C57BL/6 mice, intramuscular injection of glycerol induced AKI, which was partially prevented by G-CSF pretreatment. Consistently, glycerol-induced renal tissue damage was ameliorated by G-CSF. In addition, animal survival following the glycerol injection was improved from ∼30 to ∼70% by G-CSF. In cultured renal tubular cells, hemin-induced apoptosis was also suppressed by G-CSF. Interestingly, G-CSF induced heme oxygenase-1 (HO-1, a critical enzyme for heme/hemin degradation and detoxification) in both cultured tubular cells and mouse kidneys. Blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) could largely diminish the protective effects of G-CSF. Together, these results demonstrated the renoprotective effects of G-CSF in rhabdomyolysis-associated AKI. Notably, G-CSF may directly protect against tubular cell injury under the disease condition by inducing HO-1.

scholarly journals Renal Tubular Epithelial TRPA1 Acts as An Oxidative Stress Sensor to Mediate Ischemia-Reperfusion-Induced Kidney Injury through MAPKs/NF-κB Signaling

2021 ◽  
Vol 22 (5) ◽  
pp. 2309 ◽  
Author(s):  
Chung-Kuan Wu ◽  
Chia-Lin Wu ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Oxidative Stress ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Stress Sensor ◽  
Renal Tubular Cells ◽  
Renal Tubular

Oxidative stress and inflammation play important roles in the pathophysiology of acute kidney injury (AKI). Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable ion channel that is sensitive to reactive oxygen species (ROS). The role of TRPA1 in AKI remains unclear. In this study, we used human and animal studies to assess the role of renal TRPA1 in AKI and to explore the regulatory mechanism of renal TRPA1 in inflammation via in vitro experiments. TRPA1 expression increased in the renal tubular epithelia of patients with AKI. The severity of tubular injury correlated well with tubular TRPA1 or 8-hydroxy-2′-deoxyguanosine expression. In an animal model, renal ischemia-reperfusion injury (IR) increased tubular TRPA1 expression in wild-type (WT) mice. Trpa1−/− mice displayed less IR-induced tubular injury, oxidative stress, inflammation, and dysfunction in kidneys compared with WT mice. In the in vitro model, TRPA1 expression increased in renal tubular cells under hypoxia-reoxygenation injury (H/R) conditions. We demonstrated that H/R evoked a ROS-dependent TRPA1 activation, which elevated intracellular Ca2+ level, increased NADPH oxidase activity, activated MAPK/NF-κB signaling, and increased IL-8. Renal tubular TRPA1 may serve as an oxidative stress sensor and a crucial regulator in the activation of signaling pathways and promote the subsequent transcriptional regulation of IL-8. These actions might be evident in mice with IR or patients with AKI.

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