Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury

2018 ◽  
Vol 132 (7) ◽  
pp. 825-838 ◽  
Author(s):  
Yunwen Yang ◽  
Xiaowen Yu ◽  
Yue Zhang ◽  
Guixia Ding ◽  
Chunhua Zhu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Target Genes ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Protective Effects ◽  
Low Oxygen ◽  
Periodic Acid Schiff ◽  
Tubular Cells ◽  
Kidney Morphology

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cis-diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro, FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI.

Hesperidin Shows Protective Effects on Renal Function in Ischemia-induced Acute Kidney Injury (Sprague-Dawley Rats)

2019 ◽  
Vol 51 (8) ◽  
pp. 2838-2841
Author(s):  
Won Seo Park ◽  
Min Su Park ◽  
Sang Wook Kang ◽  
Seul A. Jin ◽  
Youngchul Jeon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Kidney Injury ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

scholarly journals Methane-Rich Saline Ameliorates Sepsis-Induced Acute Kidney Injury through Anti-Inflammation, Antioxidative, and Antiapoptosis Effects by Regulating Endoplasmic Reticulum Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yifan Jia ◽  
Zeyu Li ◽  
Yang Feng ◽  
Ruixia Cui ◽  
Yanyan Dong ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endoplasmic Reticulum ◽  
Periodic Acid ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Acute Injury ◽  
Control Group ◽  
Tunel Staining ◽  
Periodic Acid Schiff ◽  
Surgery Group

Sepsis-induced acute kidney injury (AKI) is a severe complication of sepsis and an important cause of mortality in septic patients. Previous investigations showed that methane had protective properties against different diseases in animal models. This study is aimed at investigating whether methane-rich saline (MRS) has a protective effect against sepsis-induced AKI. Sepsis was induced in wild-type C57BL/6 mice by cecal ligation and puncture (CLP), and the mice were divided into three groups: a sham control group (sham), a surgery group with saline intraperitoneal injection (i.p.) treatment (CLP + NS), and a surgery group with MRS i.p. treatment (CLP + MRS). 24 h after the establishment of the sepsis, the blood and kidney tissues of mice in all groups were collected. According to the serum levels of blood urea nitrogen (BUN) and creatinine (CRE) and a histologic analysis, which included hematoxylin-eosin (H&E) staining and periodic acid-Schiff (PAS) staining, MRS treatment protected renal function and tissues from acute injury. Additionally, MRS treatment significantly ameliorated apoptosis, based on the levels of apoptosis-related protein makers, including cleaved caspase-3 and cleaved PARP, and the levels of Bcl-2/Bax expression and TUNEL staining. In addition, the endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)/caspase-12 apoptosis signaling pathway was significantly suppressed in the CLP + MRS group. The levels of inflammation and oxidative stress were also reduced after MRS treatment. These results showed that MRS has the potential to ameliorate sepsis-induced acute kidney injury through its anti-inflammatory, antioxidative, and antiapoptosis properties.

scholarly journals Role of spleen-derived CD11b+Gr-1+ cells in sepsis-induced acute kidney injury

2020 ◽  
Vol 43 (2) ◽  
pp. E24-34
Author(s):  
Yuhan Cao ◽  
Qiancheng Xu, MD Xu ◽  
Can Liu ◽  
Cong Fu
Keyword(s):  
Acute Kidney Injury ◽  
Interleukin 6 ◽  
Caspase 3 ◽  
Periodic Acid ◽  
Plasma Concentrations ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Interleukin 1Β ◽  
Periodic Acid Schiff ◽  
Splenic Cd11b

Purpose: CD11b+Gr-1+ cells play a key role in inflammation and the purpose of this study was to determine whether splenic CD11b+Gr-1+ cells are mobilized to the kidney and lead to acute kidney injury during sepsis. Methods: The sepsis model was generated via cecum ligation and puncture (CLP). The mice were randomly distributed into control, sham operated, CLP and CLP+splenectomy (CLPS) groups (n=5–10/group). The percentage of CD11b+Gr-1+ cells in circulating, bone marrow and spleen were determined. Plasma concentrations of interleukin-6, interleukin-1β, creatinine (Cr) and neutrophil gelatinase-associated lipocalin were measured. CD11b+Gr-1+ cells were detected by immunofluorescence and qRT-PCR. Hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) were performed. Expression of mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α) and cleaved caspase-3 was measured. Results: The percentage of CD11b+Gr-1+ cells in blood was significantly higher in the CLP group and lower in CLPS group. CD11b+Gr-1+ cells in the spleen were significantly lower in the CLP group. In the CLP group, the plasma concentrations of interleukin-6, interleukin-1β, Cr and neutrophil gelatinaseassociated lipocalin were higher. The expression of Gr-1 and CD11b were higher in CLP. The CD11b+Gr-1+ cells were detected in the kidneys of the CLP group. HE, PAS and TUNEL showed inflammatory cell infiltration and cell apoptosis in CLP. Western blot indicated dephosphorylation of mTOR, down-expression of HIF-1α and increased expression of cleaved caspase-3 in sepsis kidney. Conclusion: Splenic CD11b+Gr-1+ cells migrated to the kidney in sepsis, which led to acute kidney injury via the inhibition of mTOR/HIF-1α.

scholarly journals The exosomes derived from urine of premature infants target MAPK8 via miR-30a-5p to protect cisplatin-induced acute kidney injury in mice

2021 ◽  
Author(s):  
Mingming Ma ◽  
Qiao Luo ◽  
Lijing Fan ◽  
Weilong Li ◽  
Qiang Li ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Premature Infants ◽  
Target Genes ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Hk2 Cells

Aim: Acute kidney injury (AKI), a global public health issue, not only causes millions of deaths every year, but is also a susceptible factor for chronic kidney disease (CKD). Nephrotoxic drugs are an important cause of AKI. There is still a lack of effective and satisfactory prevention method in clinical practice. This study investigated the protective effect of the exosomes derived from urine of premature infants on cisplatin-induced acute kidney injury. Methods: Isolation of exosomes from fresh urine of premature infants: The characteristics of exosomes were determined by flow cytometry, transmission electron microscopy and Western blotting. A C57BL/6 mice model of cisplatin-induced acute kidney injury was established. The mice in the experimental group were given 100ug exosomes dissolved in 200ul solution. The mice in the control group were given normal saline (200ul). These treatments were performed 24 hours after AKI was induced by intraperitoneal injection of cisplatin. To evaluate renal function, blood was drawn 24 hours after AKI model was established and serum creatinine (sCr) was measured. The mice were euthanized 72 hours after exosome treatment. The kidneys were collected for pathological examination, RNA and protein extraction, and the evaluation of renal tubular damage and apoptosis. In the in-vitro experiment, human renal cortex/proximal tubular cells (HK2) was induced by cisplatin to assess the protective ability of the exosomes derived from urine of premature infants. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blotting were used to evaluate the effect of exosomes treatment on the apoptosis of HK2 cells induced by cisplatin. Exosome microRNA sequencing technology and bioinformatics analysis method were applied to investigate the miRNAs enriched in exosomes and their target genes. The dual luciferase gene reporter system was used to detect the interaction of target genes. Results: Treatment of exosomes derived from urine of premature infants could decrease the level of serum creatinine and the apoptosis of renal tubular cell, inhibit the infiltration of inflammatory cell, protect mice from acute kidney injury induced by cisplatin and reduce mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes derived from urine of premature infants. It protected HK2 cells from cisplatin-induced apoptosis by targeting and down-regulating the 3'UTR of mitogen-activated protein kinases (MAPK8) mRNA. Conclusions: According to our results, the exosomes derived from urine of premature infants alleviated cisplatin-induced acute kidney injury in mice and inhibited the apoptosis of human proximal tubular cells (HK2) induced by cisplatin in vitro. MiR-30a-5p in exosomes inhibited cisplatin-induced MAPK activation, ameliorated apoptosis, and protected renal function. The exosomes derived from urine of premature infants provided a promising acellular therapy for AKI.

VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury

2011 ◽  
Vol 300 (1) ◽  
pp. F207-F218 ◽  
Author(s):  
Li Yuan ◽  
Min-Juan Wu ◽  
Hong-Yu Sun ◽  
Jun Xiong ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Kidney Injury ◽  
Capillary Density ◽  
Tubular Structure ◽  
Protective Effects ◽  
Cell Protection ◽  
Nude Mouse Model ◽  
Renal Tubular

The implantation of mesenchymal stem cells (MSC) has been reported as a new technique to restore renal tubular structure and improve renal function in acute kidney injury (AKI). Vascular endothelial growth factor (VEGF) plays an important role in the renoprotective function of MSC. Whether upregulation of VEGF by a combination of MSC and VEGF gene transfer could enhance the protective effect of MSC in AKI is not clear. We investigated the effects of VEGF-modified human embryonic MSC (VEGF-hMSC) in healing cisplatin-injured renal tubular epithelial cells (TCMK-1) with a coculture system. We found that TCMK-1 viability declined 3 days after cisplatin pretreatment and that coculture with VEGF-hMSC enhanced cell protection via mitogenic and antiapoptotic actions. In addition, administration of VEGF-hMSC in a nude mouse model of cisplatin-induced kidney injury offered better protective effects on renal function, tubular structure, and survival as represented by increased cell proliferation, decreased cellular apoptosis, and improved peritubular capillary density. These data suggest that VEGF-modified hMSC implantation could provide advanced benefits in the protection against AKI by increasing antiapoptosis effects and improving microcirculation and cell proliferation.

scholarly journals Citrate shows protective effects on cardiovascular and renal function in ischemia-induced acute kidney injury

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Anja Bienholz ◽  
Jonas Reis ◽  
Pinar Sanli ◽  
Herbert de Groot ◽  
Frank Petrat ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Kidney Injury ◽  
Protective Effects

scholarly journals Platelet-rich Plasma Enhanced MSCs Repair for Glycerin-induced Acute Kidney Injury via AKT/Rab27 Paracrine Pathway

2020 ◽  
Author(s):  
Cheng Ji ◽  
Jiahui Zhang ◽  
Hui Shi ◽  
wanzhu Liu ◽  
Fengtian Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Kidney Injury ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Platelet Rich Plasma ◽  
Kidney Injury ◽  
Human Umbilical Cord ◽  
Tubular Cells ◽  
Renal Tubular Cells

Abstract Background: Acute kidney injury (AKI) was defined by rapid deterioration of renal function, as a common complication in hospitalized patients. Among the recent therapeutic options, mesenchymal stem cells (MSCs) were considered a promising strategy for damaged tissues repair. Platelet rich plasma (PRP) regulates stromal cells to repair tissue damage through the release of growth factors. Here we proposed a possible therapeutic use of human umbilical cord mesenchymal stem cells stimulated by platelet-rich plasma (PRP-MSCs) in a murine model of acute renal injury generated by glycerin injection.Methods: In vivo, we constructed cisplatin-induced acute kidney injury rat models. On day 1 post injury, rat received a tail vein injection of 1×106 MSCs and 1×106 PRP-MSCs. All animals were sacrificed at Day 3 after glycerin injection. Renal function (serum BUN, Creatinine), histopathological structure changes and tubular cells apoptosis were evaluated. In vitro experiment, 50 μmol/L of glycerin treated NRK-52E for 12h were incubated with MSC or PRP-MSC for 24h in transwell co-culture system. Cells were harvested for apoptosis assay, immunofluorescence assay, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR).Results: In vivo and vitro studies confirmed that the PRP induced YAP nucleus expression to promoting the proliferation and reinforces the stemness of MSCs, and stimulated the paracrine exosomes of MSCs by activating AKT/Rab27 signaling pathway to inhibiting the apoptosis of renal tubular cells. Conclusions: Our results revealed a novel potential use of PRP-MSCs as therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor PRP-MSCs.

CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

2013 ◽  
Vol 305 (7) ◽  
pp. F1064-F1073 ◽  
Author(s):  
Nanmei Liu ◽  
Andreas Patzak ◽  
Jinyuan Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Nuclear Antigen ◽  
Tubular Cells

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves the repair ability of BMSCs and that this is related to increased homing of BMSCs and increased release of cytokines. Hypoxia/reoxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs, and CXCR4-BMSCs were cocultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death, and expressions of cleaved caspase-3 and Bcl-2 in cocultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions of the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation, and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18+ cells in BMSCs, null-BMSCs, and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of bone morphogenetic protein-7, hepatocyte growth factor, and interleukin 10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In cocultured HR-RTECs the proportions of PCNA+ cells and Bcl-2 expression were enhanced; however, the proportion of annexin V+ cells and expression of cleaved caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, which was associated with improved renal function, reduced acute tubular necrosis scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy for AKI.

scholarly journals Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

2020 ◽  
Vol 21 (19) ◽  
pp. 7236
Author(s):  
Lana Nežić ◽  
Ranko Škrbić ◽  
Ljiljana Amidžić ◽  
Radoslav Gajanin ◽  
Zoran Milovanović ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cytochrome C ◽  
Renal Damage ◽  
Structural Changes ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protective Effects ◽  
Inflammatory Injury ◽  
Tubular Cells

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs (p  <  0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.

scholarly journals The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury

2021 ◽  
Author(s):  
Alexis Piedrafita ◽  
Stéphane Balayssac ◽  
Nicolas Mayeur ◽  
Stéphane Gazut ◽  
Julia Grossac ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Messenger Rna ◽  
Periodic Acid ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Fluorescein Isothiocyanate ◽  
Published Data ◽  
Ischaemia Reperfusion Injury ◽  
Periodic Acid Schiff ◽  
Significant Difference

Abstract Background Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD+) production was identified after acute kidney injury (AKI), leading to the hypothesis that supplementation with NAM may increase the kidney NAD+ content, rescuing tryptophan pathways and subsequently improving kidney outcomes. Methods Urinary measurement of tryptophan and kynurenin using liquid chromatography–mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia–reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used. Results We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve [AUC] 0.82 [95% confidence interval (CI) 0.75–0.88] and 0.75 [0.68–0.83], respectively} and severe KDIGO Stages 2–3 AKI [AUC 0.71 (95% CI 0.6–0.81) and 0.66 (0.55–0.77), respectively]. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin–fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid–Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD+ kidney content. Conclusion Notwithstanding the potential role of NAM supplementation in the setting of basal NAD+ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients.

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