Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner

Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available “Western” diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.

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Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00117.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. F75-F84 ◽

Cited By ~ 100

Author(s):

Ju-Rong Yang ◽

Feng-Hua Yao ◽

Jian-Guo Zhang ◽

Zhi-Yong Ji ◽

Kai-Long Li ◽

...

Keyword(s):

Epithelial Cells ◽

Er Stress ◽

Renal Tubule ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Tissue ◽

Renal Ischemia ◽

Cell Death Pathway

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.

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Ascorbic acid improves renal microcirculatory oxygenation in a rat model of renal I/R injury

Journal of Translational Internal Medicine ◽

10.1515/jtim-2015-0011 ◽

2015 ◽

Vol 3 (3) ◽

pp. 116-125 ◽

Cited By ~ 3

Author(s):

Bulent Ergin ◽

Coert J. Zuurbier ◽

Rick Bezemer ◽

Asli Kandil ◽

Emre Almac ◽

...

Keyword(s):

Oxidative Stress ◽

Ascorbic Acid ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Tissue ◽

Control Group ◽

Free Oxygen Radicals ◽

Time Control ◽

Inflammatory Parameters

AbstractBackground and objectives: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. Materials and methods: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. Results: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. Conclusion: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

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Targeting HIF-1α to Prevent Renal Ischemia-Reperfusion Injury: Does It Work?

International Journal of Cell Biology ◽

10.1155/2018/9852791 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Kapil Sethi ◽

Kenny Rao ◽

Damien Bolton ◽

Oneel Patel ◽

Joseph Ischia

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Arterial Occlusion ◽

Small Animal ◽

Kidney Injury ◽

Renal Ischemia ◽

Metabolic Adaptation ◽

Critical Ischemia

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

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Histone acetylation and DNA methylation in ischemia/reperfusion injury

Clinical Science ◽

10.1042/cs20180465 ◽

2019 ◽

Vol 133 (4) ◽

pp. 597-609 ◽

Cited By ~ 13

Author(s):

Jinhua Tang ◽

Shougang Zhuang

Keyword(s):

Dna Methylation ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Circulatory Arrest ◽

Kidney Injury ◽

High Morbidity ◽

Epigenetic Alterations ◽

Injury Causes ◽

Potential Therapeutics

Abstract Ischemic/reperfusion (I/R) injury causes a series of serious clinical problems associated with high morbidity and mortality in various disorders, such as acute kidney injury (AKI), myocardial infarction, ischemic stroke, circulatory arrest, and peripheral vascular disease. The pathophysiology and pathogenesis of I/R injury is complex and multifactorial. Recent studies have revealed that epigenetic regulation is critically involved in the pathogenesis of I/R-induced tissue injury. In this review, we will sum up recent advances on the modification, regulation, and implication of histone modifications and DNA methylation in I/R injury-induced organ dysfunction. Understandings of I/R-induced epigenetic alterations and regulations will aid in the development of potential therapeutics.

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Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity

AJP Renal Physiology ◽

10.1152/ajprenal.00691.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. F1494-F1502 ◽

Cited By ~ 42

Author(s):

David P. Basile ◽

Ellen C. Leonard ◽

Alisa G. Beal ◽

Devin Schleuter ◽

Jessica Friedrich

Keyword(s):

Oxidative Stress ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Oxidant Stress ◽

Kidney Injury ◽

Renal Tissue ◽

Ang Ii ◽

Tissue Slices ◽

Dual Oxidase ◽

Renal Ischemia Reperfusion Injury

ANG II is a potent renal vasoconstrictor and profibrotic factor and its activity is enhanced by oxidative stress. We sought to determine whether renal oxidative stress was persistent following recovery from acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) injury in rats and whether this resulted in increased ANG II sensitivity. Rats were allowed to recover from bilateral renal I/R injury for 5 wk and renal blood flow responses were measured. Post-AKI rats showed significantly enhanced renal vasoconstrictor responses to ANG II relative to sham-operated controls and treatment of AKI rats with apocynin (15 mM, in the drinking water) normalized these responses. Recovery from AKI for 5 wk resulted in sustained oxidant stress as indicated by increased dihydroethidium incorporation in renal tissue slices and was normalized in apocynin-treated rats. Surprisingly, the renal mRNA expression for common NADPH oxidase subunits was not altered in kidneys following recovery from AKI; however, mRNA screening using PCR arrays suggested that post-AKI rats had decreased renal Gpx3 mRNA and an increased expression other prooxidant genes such as lactoperoxidase, myeloperoxidase, and dual oxidase-1. When rats were infused for 7 days with ANG II (100 ng·kg−1·min−1), renal fibrosis was not apparent in sham-operated control rats, but it was enhanced in post-AKI rats. The profibrotic response was significantly attenuated in rats treated with apocynin. These data suggest that there is sustained renal oxidant stress following recovery from AKI that alters both renal hemodynamic and fibrotic responses to ANG II, and may contribute to the transition to chronic kidney disease following AKI.

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Plasma Concentrations of Extracellular DNA in Acute Kidney Injury

Diagnostics ◽

10.3390/diagnostics10030152 ◽

2020 ◽

Vol 10 (3) ◽

pp. 152 ◽

Cited By ~ 1

Author(s):

Jordanka Homolová ◽

Ľubica Janovičová ◽

Barbora Konečná ◽

Barbora Vlková ◽

Peter Celec ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Plasma Concentrations ◽

Kidney Injury ◽

High Sensitivity ◽

Diagnostic Methods ◽

Extracellular Dna ◽

Potential Marker

Current diagnostic methods of acute kidney injury (AKI) have limited sensitivity and specificity. Tissue injury has been linked to an increase in the concentrations of extracellular DNA (ecDNA) in plasma. A rapid turnover of ecDNA in the circulation makes it a potential marker with high sensitivity. This study aimed to analyze the concentration of ecDNA in plasma in animal models of AKI. Three different fractions of ecDNA were measured—total ecDNA was assessed fluorometrically, while nuclear ecDNA (ncDNA) and mitochondrial DNA (mtDNA) were analyzed using quantitative real-time PCR. AKI was induced using four different murine models of AKI-bilateral ureteral obstruction (BUO), glycerol-induced AKI (GLY), ischemia–reperfusion injury (IRI) and bilateral nephrectomy (BNx). Total ecDNA was significantly higher in BUO (p < 0.05) and GLY (p < 0.05) compared to the respective control groups. ncDNA was significantly higher in BUO (p < 0.05) compared to SHAM. No significant differences in the concentrations of mtDNA were found between the groups. The plasma concentrations of different fractions of ecDNA are dependent on the mechanism of induction of AKI and warrant further investigation as potential surrogate markers of AKI.

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Ischemic Preconditioning Promotes Autophagy and Alleviates Renal Ischemia/Reperfusion Injury

BioMed Research International ◽

10.1155/2018/8353987 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Ying Xie ◽

Jing Xiao ◽

Chensheng Fu ◽

Zhenxing Zhang ◽

Zhibin Ye ◽

...

Keyword(s):

Ischemic Preconditioning ◽

Caspase 3 ◽

Cell Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Beclin 1 ◽

Autophagic Flux ◽

Dependent Manner

Autophagy is important for cellular survival during renal ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) has a strong renoprotective effect during renal I/R. Our study here aimed to explore the effect of IPC on autophagy during renal I/R injury. Rats were subjected to unilateral renal ischemia with or without prior IPC. Hypoxia/reoxygenation (H/R) injury was induced in HK-2 cells with or without prior hypoxic preconditioning (HPC). Autophagy and apoptosis were detected after reperfusion or reoxygenation for different time. The results showed that the levels of LC3II, Beclin-1, SQSTM1/p62, and cleaved caspase-3 were altered in a time-dependent manner during renal I/R. IPC further induced autophagy as indicated by increased levels of LC3II and Beclin-1, decreased level of SQSTM1/p62, and accumulation of autophagosomes compared to I/R groups at corresponding reperfusion time. In addition, IPC reduced the expression of cleaved caspase-3 and alleviated renal cell injury, as evaluated by the levels of serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) in renal tissues. In conclusion, autophagy and apoptosis are dynamically altered during renal I/R. IPC protects against renal I/R injury and upregulates autophagic flux, thus increasing the possibility for a novel therapy to alleviate I/R-induced acute kidney injury (AKI).

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Restoration of Afferent Arteriolar Autoregulatory Behavior in Ischemia-Reperfusion Injury in Rat Kidneys

AJP Renal Physiology ◽

10.1152/ajprenal.00500.2020 ◽

2021 ◽

Author(s):

Wenguang Feng ◽

Colton E. Remedies ◽

Ijeoma E. Obi ◽

Stephen R. Aldous ◽

Samia I. Meera ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Polyethylene Glycol ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Microvascular Dysfunction ◽

Renal Tissue ◽

Artery Occlusion ◽

Renal Autoregulation ◽

Baseline Diameter

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR) induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60-minutes of bilateral renal artery occlusion followed by 24 hours of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65±3% of baseline diameter (13.2±0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7±0.5 µm and remained between 90-101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (Tempol or apocynin) to IR kidneys for 20 minutes increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, addition of polyethylene glycol superoxide dismutase (PEG-SOD) or polyethylene glycol catalase (PEG-catalase) to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and MCP-1 in renal tissue homogenates and this was prevented by Tempol pre-treatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.

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Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00642.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. F495-F509 ◽

Cited By ~ 116

Author(s):

Masayuki Ishihara ◽

Madoka Urushido ◽

Kazu Hamada ◽

Tatsuki Matsumoto ◽

Yoshiko Shimamura ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Light Chain ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Tubules ◽

Dependent Manner ◽

Renal Tubular

Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1α and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stress-induced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1α-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1α-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.

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Scintigraphic, histopathologic and biochemical evaluation of lycopene effects on renal ischemia reperfusion injury in rats

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh160301031s ◽

2017 ◽

Vol 145 (3-4) ◽

pp. 153-158 ◽

Cited By ~ 2

Author(s):

Murat Sadic ◽

Hasan Atilgan ◽

Arif Aydin ◽

Gökhan Koca ◽

Meliha Korkmaz ◽

...

Keyword(s):

Reperfusion Injury ◽

Sham Group ◽

Ischemia Reperfusion Injury ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Renal Tissue ◽

Renal Ischemia ◽

Control Group ◽

Albino Rats ◽

Renal Ischemia Reperfusion Injury

Introduction/Objective. Medical protection of kidneys against ischemia reperfusion injury is very important. Many agents have been used for the protection of ischemia reperfusion renal tissue injury. We aimed to evaluate the radioprotective effect of lycopene on kidneys in ischemia reperfusion injury with histopathological, biochemical, and scintigraphic parameters. Methods. Twenty-one Wistar male albino rats were divided into the following three groups: lycopene, control, and sham group. In the lycopene group, lycopene was started three days before right renal ischemia reperfusion injury and continued for 15 days. In the control group, right renal ischemia reperfusion injury was applied with no medication. In the sham group, neither right renal ischemia reperfusion injury nor medication were applied. On the 15th day, all rats were sacrificed after 99mTc-dimercaptosuccinic acid (DMSA) scintigraphies were taken. Histopathological, biochemical, and scintigraphic evaluations were made. Results. The histopathological score was lower in the lycopene group. In biochemical analysis, myeloperoxidase levels were lower in the lycopene group than in the control group, but not statistically significant. Malondialdehyde and nitrite levels were lower in the lycopene group than in the control group. The postoperative mean 99mTc-DMSA uptake values were 44.82 ? 1.84 in the lycopene group, 38.92 ? 1.17 in the control group, and 50.21 ? 1.35 in the sham group. DMSA uptake values were higher in the lycopene group than in the control group. Conclusion. Lycopene seems to be an effective agent for protection of kidneys in ischemia reperfusion injury as demonstrated by the histopathological, biochemical, and scintigraphic parameters.

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