Rat Model Of Acute Kidney Injury Research Articles

Downregulation of XIST ameliorates acute kidney injury by sponging miR-142-5p and targeting PDCD4.

Acute kidney injury (AKI) is a common kidney disease that markedly affects public health. To date, the roles of long noncoding RNA XIST in AKI are poorly understood. Here, we investigated the biological functions of XIST in AKI. We observed that XIST expression increased in patients with AKI and HK-2 cells stimulated by CoCl2 . In addition, a rat AKI model induced by ischemia-reperfusion was established. Tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2 messenger RNA expression were induced in vivo; moreover, XIST expression was upregulated. Knockdown of XIST significantly repressed CoCl2 -triggered injury in HK-2 cells. However, microRNA (miR)-142-5p, a downstream target of XIST, was downregulated in AKI. miR-142-5p was repressed by XIST and miR-142-5p could inhibit CoCl2 -induced injury in HK-2 cells. Moreover, PDCD4 expression was significantly increased in AKI. PDCD4 was predicted to be the target of miR-142-5p. Subsequently, loss of PDCD4 was able to retard injury in HK-2 cells exposed to CoCl2. Thus, we suggest that XIST regulates miR-142-5p and PDCD4, and it has the potential to function as a biomarker in therapeutic strategies for AKI.

CircMTO1 Attenuated Acute Kidney Injury Through Regulating miR-337

Acute kidney injury (AKI) is an independent risk factor for the increased risk of death in patients with sepsis. In the current study, we first investigated the expression of circMTO1 in sepsis-induced AKI, and the underlying mechanism was further elucidated. The results showed that circMTO1 expression level was significantly decreased in serums and kidney tissues of US rats and RMCs treated with LPS. Besides, circMTO1 overexpression promoted cell viability, suppressed cell apoptosis and cytokines production of LPS-treated RMCs. Bioinformatics analysis showed that circMTO1 served as a sponge for miR-337. Furthermore, circMTO1 could inhibit the expression of KLF6. Altogether, our study first reported that circMTO1 expression was decreased in sepsis-induced AKI rat models and RMCs treated with LPS. CircMTO1 overexpression could attenuate AKI development by sponging miR-337 and regulating KLF6 expression, which may provide new ideas for evaluation the pathogenesis and the treatment of sepsis-induced AKI.

Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation

Nowadays, immune diseases are a large burden in healthcare. Mesenchymal stem cells (MSCs) have prominent ability in immunomodulation and have been applicated on treating many immune-related diseases. However, the clinical outcomes can be disparate and sometimes completely counterproductive beyond explanation of cell heterogeneity. The theory of immunomodulation plasticity in MSCs has then emerged to explain that MSCs can be induced into proinflammatory MSC1 or anti-inflammatory MSC2 responding to different immune environment. It would be safer and more efficient if we could induce MSCs into a certain immune phenotype, in most cases MSC2, prior to medical treatment. In this study, we screened and identified a classical FDA-approved drug, chlorzoxazone (CZ). Unlike traditional method induced by IFN-γ, CZ can induce MSC into MSC2 phenotype and enhance the immunosuppressive capacity without elevation of immunogenicity of MSCs. CZ-treated MSCs can better inhibit T cells activation and proliferation, promote expression of IDO and other immune mediators in vitro, and alleviate inflammatory infiltration and tissue damage in acute kidney injury rat model more effectively. Moreover, we discovered that CZ modulates phosphorylation of transcriptional factor forkhead box O3 (FOXO3) independent of classical AKT or ERK signaling pathways, to promote expression of downstream immune-related genes, therefore contributing to augmentation of MSCs immunosuppressive capacity. Our study established a novel and effective approach to induce MSC2, which is ready for clinical application.

Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model

Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases. To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies. (i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®. Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin. All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.

Is C-type natriuretic peptid level can be an early indicator for acute kidney injury?

Acute kidney injury (AKI) is defined as a reduction of renal function in hours, including both structural damage and loss of function. There are limited number of biomarkers for early detection and staging of severity. C-type natriuretic peptide (CNP) has been detected in at several tissues. We aimed to evaluate plasma CNP and creatinine levels correlated with duration of ischemia in an experimentally induced AKI rat model. Forty male Sprague-Dawley type rats (aged 8 to 12 weeks, weighing 250-350 g) were used. The animals were randomly seperated into 4 groups: Group 1(n:10): Only laparotomy was performed. The left renal artery was clamped for 3, 6 and 9 hours in groups 2 ( n:10), 3 (n:10) and 4 (n:10) respectively. CNP and creatinine levels were measured in serum samples from rats. A significant increase in creatinine levels was determined in group 2 according to group 1 (p=0.006). The mean plasma creatinine values in group 3 and 4 were decreased compared to group 2 but this difference was not statistically significant (p=0.0862). The mean CNP level in Group 2 (39.5 ± 7.93 mg/dl) was found numerically higher than group 1 (37.90 ± 5.38mg/dl). There was a statistically insignificant decrease in mean CNP levels in group 3 and 4 compared with group 2. Renal ischemia increases the level of CNP. Although the increase in CNP levels is not significant, it can be said that clinical and experimental studies evaluating the timing of ischemia involving different durations should be performed.

Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19

The characteristics of mesenchymal stem cells (MSCs) in the repair of acute kidney injury (AKI) have been extensively studied. However, some potential molecular mechanisms remain indistinct. The aim of this study was to combine published microRNA (miRNA) transcriptional profiling with quantitative proteomic analyses to reveal specific miRNAs or genes for MSC-based therapy in AKI. Transcriptome data containing significantly changed miRNAs in renal tissue from AKI mice treated with and without MSCs were downloaded. Proteomics resources were downloaded from a human proximal renal tubule cell line (HK-2) that served as a good in vitro model for AKI treated with MSCs. We connected the proteomics data with transcriptional records based on miRNA function. Differentially expressed genes (DEGs) were sorted. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted, and protein-protein interaction (PPI) chains were formed. The genes identified in the analyses were verified in a cisplatin-induced AKI rat model and in HK-2 cells exposed to cisplatin and cocultured with MSCs. A total of 207 specific DEGs were sorted. The ribosomal pathway was identified in pathway enrichment, and ribosomal proteins were identified from the PPI network complex. The targeting of the microRNAs, miR-107 to RPS19, was directly verified by the dual-luciferase method. miR-107 knockdown induced RPS19 expression, protected HK-2 cells from cisplatin-induced apoptosis, and promoted cell proliferation. By analyzing comprehensive bioinformatics data, we have confirmed the DEGs and pathways in AKI treated with MSCs. Bone marrow-derived MSCs reduce miR-107 expression and increase RPS19 expression by repressing the proliferation of cisplatin-induced AKI cells and initiating apoptosis.

Therapeutic Effects of Human Urine-Derived Stem Cells in a Rat Model of Cisplatin-Induced Acute Kidney Injury In Vivo and In Vitro.

Acute kidney injury (AKI) is an extremely dangerous clinical syndrome with high morbidity and mortality. Stem cell-based therapies have shown great promise for AKI treatment. Urine-derived stem cells (USCs) are a novel cell source in tissue engineering and cell therapy which provide advantages of simple, noninvasive, and low-cost harvest methods, efficient proliferation, and multi-differentiation potential. Here, we described the therapeutic effects of USCs in a rat model of cisplatin-induced AKI as a novel therapy. In vivo, the intravenous administration of USCs alleviated the renal functional damage in AKI rats, for the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were significantly decreased. The USCs-treated group also exhibited improved histological and ultrastructural changes, promoted proliferation, and inhibited apoptosis in renal tissues. After the USC therapy, the expression levels of proinflammatory cytokines (TNF-α and IL-6) and apoptosis-related proteins (BAX and cleaved caspase-3) were downregulated. In addition, the presence of a few GFP-labeled USCs was confirmed in rat renal tissues. In vitro, rat tubular epithelial (NRK-52E) cells were incubated with cisplatin to induce cell damage and then cocultured with USCs. After coculture with USCs, the cisplatin-induced NRK-52E cells showed higher cell viability and a lower apoptosis ratio than those of the control group, and cell cycle arrest was improved. In conclusion, our results demonstrated that USC therapy significantly improved the renal function and histological damage, inhibited the inflammation and apoptosis processes in the kidney, and promoted tubular epithelial proliferation. Our study exhibited the potential of USCs in the treatment of AKI, representing a new clinical therapeutic strategy.

MicroRNA-188 aggravates contrast-induced apoptosis by targeting SRSF7 in novel isotonic contrast-induced acute kidney injury rat models and renal tubular epithelial cells.

Contrast media (CM) is widely used in cardiac catheterization; however, it may cause contrast-induced acute kidney injury (CI-AKI) which severely increases mortality. MicroRNA (miRNA) has been found to participate in the process of acute kidney injury (AKI), and this discovery has great potential for diagnosis and treatment. However, the role of miRNA in CI-AKI is still unclear. This study aimed to investigate the regulatory effect miRNAs exert in CI-AKI. We established a novel, representative, isotonic CI-AKI model by using CM iodixanol, a CM which is commonly used in clinic. Next-generation sequencing and reverse transcription polymerase chain reaction (RT-qPCR) were performed to determine the expression of miRNA-188 in CI-AKI. Western blot analysis of the apoptosis regulator protein and TUNEL assay were ordered to evaluate apoptosis. Bioinformatics and double luciferin reporter gene assay were performed to predict and to confirm the interaction between microRNA-188 and SRSF7. The novel isotonic CI-AKI rat model we established exhibited typical characteristics of CI-AKI in serum creatinine, cystatin C, HE staining, and under electron microscope observation. Sequencing and RT-qPCR demonstrated that miRNA-188 was significantly up-regulated both in CI-AKI rat and HK-2 cell models while overexpression of miRNA-188 significantly aggravated apoptosis in CI-AKI cell models. SRSF7 was identified as a direct target gene of miRNA-188, and dual luciferase reporter assay determined the direct interaction between SRSF7 and miRNA-188. In addition, SRSF7 silencing reduced the cell viability rate of the CI-AKI cell model. The present study's findings indicate that miRNA-188 aggravated contrast-induced apoptosis by regulating SRSF7, which may serve as a potential drug target for CI-AKI intervention.

Inhibition of miR-155 Ameliorates Acute Kidney Injury by Apoptosis Involving the Regulation on TCF4/Wnt/β-Catenin Pathway

Background: Acute kidney injury (AKI) is a complex clinical disorder with sudden decay in renal function. Ischemia-reperfusion injury (IRI) has been regarded as the main etiology for the occurrence of AKI. MicroRNAs have been consistently shown to be involved AKI. Objectives: We aimed to investigate the role of miR-155 in AKI and its underlying mechanism. Methods: Ischemia-reperfusion (I/R)-induced AKI rat model and hypoxia-reoxygeneration (H/R)-induced NRK-52E cell model were established. The concentrations of serum creatinine and blood urea nitrogen were measured to evaluate renal function. Hematoxylin and eosin staining and TUNEL assay were performed to assess the severity of kidney injury. Additionally, quantitative real-time-PCR and western blot analysis were subjected to determine the expression of miR-155, TCF4, and apoptosis-related proteins, respectively. Moreover, cell proliferation and apoptosis were evaluated by Cell Counting Kit-8, bromodeoxyuridine, and flow cytometry analyses, respectively. Luciferase reporter assay was used to validate the direct targeting of TCF4 with miR-155. The protein levels of TCF4 and its downstream proteins in cells were measured by western blot. Results: The expression level of miR-155 was upregulated in both I/R-induced AKI rat model and H/R-treated NRK-52E cells. Moreover, overexpression of miR-155 promoted H/R-induced NRK-52E cells apoptosis and suppressed cell proliferation, while inhibition of miR-155 expression exerted opposite effects. Additionally, TCF4 was identified as a target of miR-155, of which expression was downregulated both in vivo and in vitro. Furthermore, the activity of Wnt/β-catenin signaling pathway was promoted following overexpression of TCF4 in NRK-52E cells, and this effect was attenuated by the increasing miR-155 expression. Conclusion: We demonstrated that miR-155 exacerbated AKI involving the targeting and regulation of TCF4/Wnt/β-catenin signaling pathway, indicating a novel regulatory network and elucidating a potential target for IRI-induced AKI treatment.

Protective effect of anisodamine in rats with glycerol-induced acute kidney injury

BackgroundAnisodamine is used for the treatment of reperfusion injury in various organs. In this study, we investigated the effectiveness and mechanisms of action of anisodamine in promoting recovery from glycerol-induced acute kidney injury (AKI).MethodsWe compared the protective effects of atropine and anisodamine in the rat model of glycerol-induced AKI. We examined signaling pathways involved in oxidative stress, inflammation and apoptosis, as well as expression of kidney injury molecule-1 (KIM-1). Renal injury was assessed by measuring serum creatinine and urea, and by histologic analysis. Rhabdomyolysis was evaluated by measuring creatine kinase levels, and oxidative stress was assessed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels in kidney tissues. Inflammation was assessed by quantifying interleukin 6 (IL-6) and CD45 expression. Apoptosis and necrosis were evaluated by measuring caspase-3 (including cleaved caspase 3) and RIP3 levels, respectively.ResultsGlycerol administration resulted in a higher mean histologic damage score, as well as increases in serum creatinine, urea, creatine kinase, reactive oxygen species (ROS), MDA, IL-6, caspase-3 and KIM-1 levels. Furthermore, glycerol reduced kidney tissue SOD activity. All of these markers were significantly improved by anisodamine and atropine. However, the mean histologic damage score and levels of urea, serum creatinine, creatine kinase, ROS and IL-6 were lower in the anisodamine treatment group compared with the atropine treatment group.ConclusionPretreatment with anisodamine ameliorates renal dysfunction in the rat model of glycerol-induced rhabdomyolytic kidney injury by reducing oxidative stress, the inflammatory response and cell death.

Non-coding RNA-Associated ceRNA Networks in a New Contrast-Induced Acute Kidney Injury Rat Model

Contrast-induced acute kidney injury (CI-AKI) is a severe complication of intravascular applied radial contrast media, and recent progress in interventional therapy and angiography has revived interest in explaining detailed mechanisms and developing effective treatment. Recent studies have indicated a potential link between CI-AKI and microRNA (miRNA). However, the potential non-coding RNA-associated-competing endogenous RNA (ceRNA) pairs involved in CI-AKI still remain unclear. In this study, we systematically explored the circRNA or lncRNA-associated-ceRNA mechanism in a new rat model of CI-AKI through deep RNA sequencing. The results revealed that the expression of 38 circRNAs, 12 lncRNAs, 13 miRNAs and 127 mRNAs were significantly dysregulated. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses for mRNAs with significantly different expression and then constructed comprehensive circRNA or lncRNA-associated ceRNA networks in kidney of CI-AKI rats. Thereafter, two constructed ceRNA regulatory pathways in this CI-AKI rat model—novel_circ_0004153/rno-miR-144-3p/Gpnmb or Naglu and LNC_000343/rno-miR-1956-5p/KCP—were validated by real-time qPCR. This study is the first one to provide a systematic dissection of non-coding RNA-associated ceRNA profiling in kidney of CI-AKI rats. The selected non-coding RNA-associated ceRNA networks provide new insight for the underlying mechanism and may profoundly affect the diagnosis and therapy of CI-AKI.

Rat mRNA expression profiles associated with inhibition of ischemic acute kidney injury by losartan.

Objective: Losartan was reported to inhibit the progression of acute kidney injury (AKI), but little is known about the underlying pharmacological mechanisms. In the present study, the mRNA expression profiles in ischemic AKI rat kidney altered by losartan treatment were analyzed by next-generation deep sequencing technology.Methods: Ischemia and reperfusion treatment was applied to induce AKI in Sprague–Dawley (SD) rats. The urea and creatinine contents in rat blood were measured. H&E staining was performed to evaluate the histological alteration of rat kidney tissues under a microscope. The TUNEL method was applied to analyze apoptosis in rat kidney tissues. The mRNA profiles in rat kidney were analyzed using next-generation deep sequencing. Differential gene expression was confirmed by quantitative qRT-PCR.Results: The rat model of AKI induced by ischemia and reperfusion showed significant increases in urea and creatinine levels, accompanied by a disrupted kidney tubular structure and renal cell apoptosis. Losartan treatment effectively inhibited the changes in urea and creatinine, tubular structure, and apoptosis in AKI rat kidney. A large number of mRNAs were found to be differentially expressed in the kidneys of AKI rats treated with losartan, which are involved in multiple processes and signaling pathways. The expression of nine differentially expressed genes such as monocyte chemoattractant protein-1 (CCL2) and suppressor of cytokine signaling 3 (SOCS3) was confirmed by qRT-PCR and Western blot.Conclusion: Losartan caused significant alterations in the gene expression profile in AKI rat kidney, which mediated its anti-AKI effects.

Therapeutic effects of human stem cells in experimentally induced acute kidney injury in rats

Objective The aim of this study was to evaluate the effect of stem cell therapy in drug-induced acute kidney injury in rats. Background Acute kidney injury (AKI) is defined as a rapid decrease in renal functions within few days; thus drug-induced AKI is a frequent entity in clinical medicine. Stem cell therapy provides a hopeful prospective for injured tissues and for repairing damaged organs. Materials and methods A total of 30 male Swiss albino rats were used in the present study. The animals were randomly divided into three groups. Group I: control group (10 rats). Group II: AKI group (10 rats), gentamicin-induced AKI rat models were used. Group III: stem-cell-treated AKI group (10 rats). Rats with established AKI were injected with CD34-positive stem cells. The three studied groups were assessed for serum urea, blood urea nitrogen, serum creatinine, and kidney injury molecule 1 (KIM-1). At the end, all the rats were killed and their kidneys were excised for histopathology and immunohistochemical studies. Results Serum KIM-1 level was significantly higher in the AKI group in comparison with both control group and stem-cell-treated group (P = 0.001), whereas no statistically significant difference was found between control group and stem-cell-treated group regarding serum KIM-1 level (P = 0.755). The results of the immunohistopathological studies have shown no significant changes between control group and AKI-stem-cell-treated group. Conclusion This study showed that AKI markers improved after treatment by stem cells in AKI-induced group.

IGFBP2 is a potential biomarker in acute kidney injury (AKI) and resveratrol-loaded nanoparticles prevent AKI.

This study aims to determine whether insulin-like growth factor binding protein2 (IGFBP2) is a useful biomarker for early diagnosis of acute kidney injury (AKI), evaluate the therapeutic effects of resveratrol-loaded nanoparticles (Res-NPs), and investigate the possible underlying mechanisms in a rat model of AKI induced by IRI. Forty male Sprague–Dawley rats were randomly divided into four groups (10 animals per group): sham, IRI control, resveratrol, and Res-NPs injection. Kidney injury and the effects of Resveratrol and Res-NPs were determined by histological examination, renal function, cell apoptosis profile, and gene expression. Changes in IGFBP2 were similar with the pattern of well-known renal biomarkers, namely, kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, in all groups. Compared with the IRI control and resveratrol groups, the Res-NPs groups displayed significantly reduced apoptotic rate, reactive oxygen species level, and malondialdehyde content, downregulated protein expression levels of Caspase3 and Bax with increased antioxidant glutathione peroxidase level, and upregulated expression of Bcl-2 protein. Thus, IGFBP2 may serve as a promising novel biomarker of AKI, and Res-NPs may prevent kidney injury from ischemia/reperfusion in a rat model.

MiR-214 ameliorates acute kidney injury via targeting DKK3 and activating of Wnt/\u03b2-catenin signaling pathway

BackgroundmiR-214 was demonstrated to be upregulated in models of renal disease and promoted fibrosis in renal injury independent of TGF-β signaling in vivo. However, the detailed role of miR-214 in acute kidney injury (AKI) and its underlying mechanism are still largely unknown.MethodsIn this study, an I/R-induced rat AKI model and a hypoxia-induced NRK-52E cell model were used to study AKI. The concentrations of kidney injury markers serum creatinine, blood urea nitrogen, and kidney injury molecule-1 were measured. The expressions of miR-214, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, were detected by RT-qPCR. The protein levels of Bcl-2, Bax, Dickkopf-related protein 3, β-catenin, c-myc, and cyclinD1 were determined by western blot. Cell apoptosis and caspase 3 activity were evaluated by flow cytometry analysis and caspase 3 activity assay, respectively. Luciferase reporter assay was used to confirm the interaction between miR-214 and Dkk3.ResultsmiR-214 expression was induced in ischemia–reperfusion (I/R)-induced AKI rat and hypoxic incubation of NRK-52E cells. Overexpression of miR-214 alleviated hypoxia-induced NRK-52E cell apoptosis while inhibition of miR-214 expression exerted the opposite effect. Dkk3 was identified as a target of miR-214. Anti-miR-214 abolished the inhibitory effects of DKK3 knockdown on hypoxia-induced NRK-52E cell apoptosis by inactivation of Wnt/β-catenin signaling. Moreover, miR-214 ameliorated AKI in vivo by inhibiting apoptosis and fibrosis through targeting Dkk3 and activating Wnt/β-catenin pathway.ConclusionmiR-214 ameliorates AKI by inhibiting apoptosis through targeting Dkk3 and activating Wnt/β-catenin signaling pathway, offering the possibility of miR-214 in the therapy of ischemic AKI.

Attenuation of pro-inflammatory cytokines and oxidative stress by misoprostol in renal ischemia/reperfusion in rats.

The ischemia/reperfusion (I/R) process alters metabolic pathways, releasing reactive oxygen species and pro-inflammatory cytokines that cause tissue necrosis and activate cellular apoptotic pathways. Misoprostol (MSP) is a prostaglandin E1 analog that has demonstrated a cytoprotective role in the I/R process. The study objective was to evaluate the effects of MSP on the regulation of pro-inflammatory and oxidative stress mediators in an I/R-induced acute kidney injury rat model. Wistar rats were divided into 3 groups. Sham and I/R were given 1 mL/day of physiological solution; MSP+I/R was given intragastric MSP (300 μg/kg) for 3 days. For I/R and MSP+IR, the renal hilum was clamped for 45 min, followed by 15 h of reperfusion. Renal function tests, pro-inflammatory cytokines, mediators of oxidative stress, and histological analysis were evaluated. Pro-inflammatory cytokine activity was significantly attenuated in the MSP+I/R group. However, there was no statistically significant difference between Sham and MSP. Regarding antioxidant activity, MSP+I/R showed a significant decrease in these mediators compared with Sham and I/R. Histologically, scarce medullary necrosis was observed with a preserved renal cortex in the MSP group.

Involvement of organic cation transporter 2 in the metformin-associated increased lactate levels caused by contrast-induced nephropathy

The application of iodinated contrast medium has become a risk factor for metformin-associated lactic acidosis (MALA), which leads to the accumulation of metformin in vivo is one of the principal reasons for MALA. However, the molecular mechanism of the adverse event is not yet clear. In this study, iohexol injection was used as a model drug. The contrast agent acute kidney injury rat model, in vivo rat pharmacokinetic study, kidney slices and HK-2 cells were performed to elucidate the pharmacokinetic molecular mechanism of accumulation of metformin caused by contrast-induced nephropathy (CIN). Plasma exposure of metformin was increased significantly in the CIN group compared with that in the normal and control groups. The AUC of metformin was from 2791 ± 382 μg min mL−1 to 4784 ± 767 μg min mL−1. The cumulative urinary excretion of metformin was also reduced in the CIN group. The uptake of metformin decreased in kidney slices in the CIN group. Compared with the normal and control groups, the blood lactate concentration was increased after intravenous administration of metformin in the CIN group followed a similar trend to the plasma concentrations of metformin. After treatment with contrast medium, the expression of OCT2 was reduced in rat kidney and HK-2 cells. These findings highlight that OCT2 deficiency was associated with increased lactate levels during metformin treatment caused by CIN.

Nephropreventing effect of hypoxia-inducible factor 1α in a rat model of ischaemic/reperfusion acute kidney injury.

Acute kidney injury (AKI) occurs in 5% of hospitalized patients and in 50% of sepsis patients with acute renal dysfunction. However, there have been no safe and effective therapeutic strategies. The hypoxia condition is closely related to renal injury and function under AKI. As hypoxia-inducible factor 1α (HIF-1α) is critical for the cellular response to hypoxia, we investigated the protective effect of HIF-1α in a rat AKI model. We found that HIF-1α injection improved the survival of rat with AKI, and the level of creatinine and blood urea nitrogen (BUN) was also increased. Our data showed that HIF-1α treatment significantly alleviated ischaemic/reperfusion injury to kidney tubules and nephrocytes. We also found the downstream factors, such as EPOR, VEGF, and PHD3, were also upregulated by HIF-1α. Finally, it was observed that HIF-1α treatment also increased the percentage of adult resident progenitor cells (ARPC) in vitro and in vivo. In conclusion, HIF-1α plays a protective role in the ischaemic AKI model through stimulating the proliferation of ARPC, and our study provided a potential therapeutic strategy for AKI.

MiR-182 enhances acute kidney injury by promoting apoptosis involving the targeting and regulation of TCF7L2/Wnt/β-catenins pathway

Acute kidney injury (AKI) is a sudden decay in renal function leading to increasing morbidity and mortality. miR-182 has been reported to be actively involved in kidney diseases. However, the function and molecular mechanism of miR-182 in AKI still need to be elucidated. The levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urine Kim-1 in I/R-induced rat AKI model were detected by a Beckman Autoanalyzer. miR-182 and transcription factor 7-like-2 (TCF7L2) mRNA expression were measured by qRT-PCR. Flow cytometry and caspase-3 colorimetry analysis were performed to determine NRK-52E cell apoptosis. Bioinformatics and dual-luciferase reporter were used to identify the interaction between miR-182 and TCF7L2. miR-182 expression was increased in both I/R-induced rat models and hypoxia-treated NRK-52E cells, and miR-182 overexpression stimulated the apoptosis of hypoxia-induced NRK-52E cells. Dual-luciferase analysis disclosed that TCF7L2 was a target of miR-182. TCF7L2 suppressed hypoxia-induced apoptosis in NRK-52E cells, and the inhibitory effect of TCF7L2 on cell apoptosis could be reversed with miR-182 restoration. Moreover, the activity of Wnt/β-catenin signaling pathway was promoted following overexpression of TCF7L2 in NRK-52E cells with hypoxia treatment, and this effect was greatly attenuated by the increased miR-182 expression. Finally, in vivo experiment also validated the alleviation of miR-182 inhibitor on I/R-induced kidney injury and apoptosis via regulating TCF7L2/ Wnt/β-catenin pathway. miR-182 exacerbated AKI involving the targeting and regulation of TCF7L2/Wnt/β-catenin signaling, unveiling a novel regulatory pathway in ischemia-reperfusion injury and elucidating a potential biomarker for AKI treatment.

MP81-02 CONTROLLED DELIVERY OF STEM CELL-DERIVED TROPHIC FACTORS TO TREAT KIDNEY INJURY

You have accessJournal of UrologyStem Cell Research: Stem Cell Research II1 Apr 2018MP81-02 CONTROLLED DELIVERY OF STEM CELL-DERIVED TROPHIC FACTORS TO TREAT KIDNEY INJURY Doosang Kim, Hyungeun Yim, Hyun Chul Chung, Brian Shing, Kyung Hyun Moon, Sunil George, John Jackson, In Kap Ko, James Yoo, and Anthony Atala Doosang KimDoosang Kim More articles by this author , Hyungeun YimHyungeun Yim More articles by this author , Hyun Chul ChungHyun Chul Chung More articles by this author , Brian ShingBrian Shing More articles by this author , Kyung Hyun MoonKyung Hyun Moon More articles by this author , Sunil GeorgeSunil George More articles by this author , John JacksonJohn Jackson More articles by this author , In Kap KoIn Kap Ko More articles by this author , James YooJames Yoo More articles by this author , and Anthony AtalaAnthony Atala More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2710AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal disease is a worldwide health issue. Besides transplantation, current therapies revolve around dialysis, which is limited to delaying disease progression through filtering metabolic wastes in blood. However, dialysis is unable to replace other renal functions, such as synthesizing erythropoietin. To address these limitations, cell-based approaches have been proposed to restore damaged kidneys as an alternative to current therapies. Particularly, recent studies have shown that stem cell-derived secretomes could enhance tissue regeneration. This study explored a gel-based delivery system for controlled delivery of trophic factors secreted from human placental stem cells (hPSC) (conditioned medium: CM) and evaluated the effect of trophic factors on renal regeneration in vitro and in vivo. METHODS hPSC were grown under normal culture environment, and conditioned media were collected and concentrated. The concentrated conditioned media containing trophic factors were combined with Platelet-rich plasma (PRP), which served as a delivery vehicle. To test the feasibility of controlled delivery, CM was encapsulated within the PRP, followed by assessing the release kinetics of CM from the gel. The gel formulation was injected into a rat acute kidney injury model for analysis. RESULTS In vitro cell viability and proliferation assays demonstrated that CM treatment significantly enhanced cell proliferation when compared with the control without CM. The release profiles show that CM can be released from PRP in a controlled manner by altering gel stiffness. An In vivo study using a rat acute kidney injury model showed that CM delivery using the gel system into the injured kidney tissue facilitated less renal tissue damage, leading to rapid functional recovery than that of saline, CM or vehicle only group. CONCLUSIONS These results suggest that the delivery of hPSC-derived trophic factors in a controlled manner may contribute to effective kidney repair from renal tissue injury. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1097 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Doosang Kim More articles by this author Hyungeun Yim More articles by this author Hyun Chul Chung More articles by this author Brian Shing More articles by this author Kyung Hyun Moon More articles by this author Sunil George More articles by this author John Jackson More articles by this author In Kap Ko More articles by this author James Yoo More articles by this author Anthony Atala More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...