scholarly journals Shen-Qi-Wan Protects the Renal Peritubular Capillary From Adenine-mediated Damage by Upregulating Aquaporin 1

2020 ◽  
Author(s):  
Yuting Bao ◽  
Yehui Zhang ◽  
Yuanxiao Yang ◽  
Xueming Chen ◽  
Luning Lin ◽  
...  
Keyword(s):  
Renal Injury ◽  
Protein Level ◽  
Kidney Injury ◽  
Trial Registration ◽  
Renal Tubules ◽  
Peritubular Capillary ◽  
Lumen Formation ◽  
Function Loss ◽  
Cell Experiment

Abstract Background：Shen-Qi-Wan (SQW), a commonly used prescription against chronic kidney disease (CKD) in Traditional Chinese Medicine (TCM), has a nephroprotective action in adenine-induced kidney injury. However, the mechanism of SQW in renal injury remains unclear.Methods: We evaluated the nephroprotective action of SQW in adenine-induced kidney injury and investigated its mechanism in vitro studies.Results: SQW supplementation could alleviate the pathological makers for CKD, ameliorate dysfunction of Hypothalamic-Pituitary-Adrenal (HPA) axis and renal function loss caused by adenine. Alternatively, SQW administration showed an ameliorating effect from the toxicity and alleviated the injury of capillaries around renal tubules instigated by adenine through increasing AQP1 mRNA and protein level. In vitro experiments, SQW medicated serum enhanced the migration and lumen formation ability of HMEC-1 cells, and significantly increased AQP1 protein level. Moreover, AQP1 knockdown efficiently inhibited migration and lumen formation ability in HMEC-1 cells which could be reversed by SQW medicated serum.Trial registration : This is an animal and cell experiment, trial registration is not necessary.Conclusion: These results suggested that SQW attenuated peritubular capillary injury in adenine induced CKD model rats through boosting angiogenesis in endothelial cell and AQP1 may be a potential target of SQW for treating renal injury.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

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 Protective role of DJ-1 in endotoxin-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F654-F663 ◽  
Author(s):  
Joseph Leeds ◽  
Yogesh Scindia ◽  
Valentina Loi ◽  
Ewa Wlazlo ◽  
Elizabeth Ghias ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Protective Role ◽  
In Vivo Model ◽  
Renal Tubules ◽  
Death Domain ◽  
Renal Tubular

Acute kidney injury (AKI) is a frequent complication of sepsis and an important cause of morbidity and mortality worldwide. A cornerstone of sepsis-associated AKI is dysregulated inflammation, leading to increased tissue oxidative stress and free radical formation, which leads to multiple forms of cell death. DJ-1 is a peroxiredoxin protein with multiple functions, including its ability to control cellular oxidative stress. Although DJ-1 is expressed prominently by renal tubules, its role in AKI has not been investigated. In the present study, we examined the effect of DJ-1 deficiency in a murine model of endotoxin-induced AKI. Endotoxemia induced greater kidney injury in DJ-1-deficient mice. Furthermore, DJ-1 deficiency increased renal oxidative stress associated with increased renal tubular apoptosis and with expression of death domain-associated protein (DAXX). Similar to the in vivo model, in vitro experiments using a medullary collecting duct cell line (mIMCD3) and cytotoxic serum showed that serum obtained from wild-type mice resulted in increased expression of s100A8/s100A9, DAXX, and apoptosis in DJ-1-deficient mIMCD3 cells. Our findings demonstrate a novel renal protective role for renal tubular DJ-1 during endotoxemia through control of oxidative stress, renal inflammation, and DAXX-dependent apoptosis.

Kidney injury molecule-1 expression in IgA nephropathy and its correlation with hypoxia and tubulointerstitial inflammation

2014 ◽  
Vol 306 (8) ◽  
pp. F885-F895 ◽  
Author(s):  
Qiongzhen Lin ◽  
Ying Chen ◽  
Jicheng Lv ◽  
Hong Zhang ◽  
Jiawei Tang ◽  
...  
Keyword(s):  
Renal Function ◽  
Iga Nephropathy ◽  
Renal Injury ◽  
Kidney Injury ◽  
Inflammatory Cells ◽  
Capillary Density ◽  
Clinicopathological Parameters ◽  
Tubulointerstitial Injury ◽  
Tubulointerstitial Inflammation

Tubulointerstitial injury plays an important role in the development and progression of chronic kidney disease (CKD). Kidney injury molecule (KIM)-1 is induced in damaged proximal tubules in both acute renal injury and CKD. However, the dynamics of KIM-1 in CKD and effects of KIM-1 expression on disease progression are unknown. Here, we aimed to determine the associations between tubular KIM-1 expression levels, renal function, and inflammation in CKD. The relationships between levels of KIM-1 and clinicopathological parameters were analyzed in patients with progressive and nonprogressive IgA nephropathy. KIM-1 expression was increased in patients with IgA nephropathy, and its expression was significantly correlated with the decrease of renal function. KIM-1 was particularly evident at the site with reduced capillary density, and KIM-1-positive tubules were surrounded by infiltrates of inflammatory cells. Using in vitro cell models, we showed that cellular stressors, including hypoxia, induced KIM-1 expression. KIM-1-expressing cells produced more chemokines/cytokines when cultured under hypoxic conditions. Furthermore, we showed that tubular cells with KIM-1 expression can regulate the immune response of inflammatory cells through the secretion of chemotactic factors. These data suggest that KIM-1-expressing epithelial cells may play a role in the pathogenesis of tubulointerstitial inflammation during chronic renal injury through the secretion of chemokines/cytokines.

scholarly journals Melatonin Alleviates Renal Injury in Mouse Model of Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Liyang Chen ◽  
Zhijian Han ◽  
Zhiguang Shi ◽  
Chao Liu ◽  
Qiulun Lu
Keyword(s):  
Renal Injury ◽  
Oxidant Stress ◽  
Mrna Level ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Role ◽  
Cecal Ligation Puncture ◽  
Species Production

Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.

scholarly journals Effects of Tristetraprolin on Doxorubicin (Adriamycin)-induced experimental nephrotic syndrome though inhibiting IL-13 /STAT6 signal pathway

2019 ◽  
Author(s):  
Qian Zhang ◽  
Ge Wu ◽  
Shiyuan Guo ◽  
Yong Liu ◽  
Zhangsuo Liu
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Epithelial Cell ◽  
Western Blot ◽  
Cell Line ◽  
Renal Injury ◽  
Kidney Injury ◽  
Adverse Outcomes ◽  
Epithelial Cell Line

Abstract Background: To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). Methods: DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of the animal groups under investigation were recorded daily throughout the experimental period. Histological changes were observed using Hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and ROS, MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, intracellular levels of oxidative stress were assessed using 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining. TTP and Kim-1 expression levels were measured by immunohistochemistry and western blot. The TNF-α, IL-1β and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected via western blot, respectively. CCK-8 was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. Results: DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Conclusion: Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.

Abstract 110: Reduced Expression, Knockout, and Pharmacological Intervention of Arhgef11 -RhoA Pathway Significantly Attenuates Renal Injury and Blood Pressure

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ashley C Johnson ◽  
David S Pasco ◽  
Michael R Garrett
Keyword(s):  
Genetic Analysis ◽  
Natural Product ◽  
Renal Injury ◽  
Substantial Reduction ◽  
Kidney Injury ◽  
Pharmacological Intervention ◽  
Nucleotide Exchange ◽  
Low Salt

Through genetic analysis of the Dahl salt-sensitive (SS) rat, a model of hypertension and chronic kidney disease (CKD), Arhgef11, a Rho guanine nucleotide exchange factor was implicated in kidney injury. Arhgef11, via exchange of GDP for GTP, plays a role in the activation of RhoA signaling cascades through a number of cell stimuli that impact cytoskeletal structure and influence cell-cell contacts and promotes cell transformation. Previously, we demonstrated that reduced Arhgef11 expression/protein function in an SS- Arhgef11 SHR -minimal congenic strain resulted in significantly decreased proteinuria, fibrosis, and improved renal hemodynamics compared to SS-WT, without impacting BP. More recently, an SS-Arhgef11 -/- knockout rat model was studied. On low-salt (0.3% NaCl), SS-Arhgef11 -/- animals demonstrated reduced proteinuria and renal injury, with no impact on BP versus SS-WT. In contrast, SS-Arhgef11 -/- animals on an elevated-salt diet (2% NaCl) demonstrated a significant (p<0.001) attenuation of proteinuria (41±7.9 mg/24 hrs.), along with a substantial reduction in BP (124±2.6 mm Hg) compared to SS-WT (119±15.3 mg/24 hrs. and 151±5.9 mm Hg). This data suggests that reduced expression/loss of Arhgef11 (on low-salt) similarly leads to renoprotection, whereas the loss of Arhgef11 (vs reduced expression) leads to blunting of salt-induced elevations in BP vs SS-WT. These animal studies, in combination with in vitro work, suggest that inhibition of Arhgef11-RhoA could be an effective therapeutic for CKD. Using an in vitro cell screen, several hundred natural product compounds were tested for ability to inhibit Arhgef11/RhoA activity and identified 3 compounds. A pilot study done using one compound (sufficient for a one-week study) was very encouraging as animals treated with XTL-019-G7 (20mg/kg/day) exhibited an ~25% reduction in proteinuria compared to vehicle (VEH) treated animals (70±8.5 versus 95±9.6 mg/24hours, p=0.07), demonstrating that in vivo testing is feasible and that the compound warrants further testing. In summary, genetic analysis of a model of CKD identified a gene/pathway involved in kidney injury that served as a target to screen natural product derived small molecules, and may ultimately lead to a new treatment for CKD.

scholarly journals WNT/β-Catenin Signaling Is Required for Integration of CD24+Renal Progenitor Cells into Glycerol-Damaged Adult Renal Tubules

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Zhao Zhang ◽  
Diana M. Iglesias ◽  
Rachel Corsini ◽  
LeeLee Chu ◽  
Paul Goodyer
Keyword(s):  
Progenitor Cells ◽  
Kidney Injury ◽  
Perinatal Period ◽  
Renal Tubules ◽  
Adult Mice ◽  
Renal Progenitor Cells ◽  
Nephron Progenitor ◽  
Canonical Wnt ◽  
Renal Progenitor

During development, nephron progenitor cells (NPC) are induced to differentiate by WNT9b signals from the ureteric bud. Although nephrogenesis ends in the perinatal period, acute kidney injury (AKI) elicits repopulation of damaged nephrons. Interestingly, embryonic NPC infused into adult mice with AKI are incorporated into regenerating tubules. Since WNT/β-catenin signaling is crucial for primary nephrogenesis, we reasoned that it might also be needed for the endogenous repair mechanism and for integration of exogenous NPC. When we examined glycerol-induced AKI in adult mice bearing aβ-catenin/TCF reporter transgene, endogenous tubular cells reexpressed the NPC marker, CD24, and showed widespreadβ-catenin/TCF signaling. We isolated CD24+cells from E15 kidneys of mice with the canonical WNT signaling reporter. 40% of cells responded to WNT3ain vitroand when infused into glycerol-injured adult, the cells exhibitedβ-catenin/TCF reporter activity when integrated into damaged tubules. When embryonic CD24+cells were treated with aβ-catenin/TCF pathway inhibitor (IWR-1) prior to infusion into glycerol-injured mice, tubular integration of cells was sharply reduced. Thus, the endogenous canonicalβ-catenin/TCF pathway is reactivated during recovery from AKI and is required for integration of exogenous embryonic renal progenitor cells into damaged tubules. These events appear to recapitulate the WNT-dependent inductive process which drives primary nephrogenesis.

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

2019 ◽  
Vol 316 (2) ◽  
pp. F382-F395 ◽  
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.

Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation

2020 ◽  
Vol 318 (4) ◽  
pp. F994-F1005
Author(s):  
Suwen Liu ◽  
Yunwen Yang ◽  
Huiping Gao ◽  
Ning Zhou ◽  
Peipei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Renal Histology ◽  
Hypoxia Reoxygenation

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

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