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

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.

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

2015 ◽  
Vol 3 (3) ◽  
pp. 116-125 ◽  
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.

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

2012 ◽  
Vol 302 (11) ◽  
pp. F1494-F1502 ◽  
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.

Renoprotective effects of prazosin on ischemia-reperfusion injury in rats

2021 ◽  
pp. 096032712199322
Author(s):  
MM Rahimi ◽  
A Bagheri ◽  
Y Bagheri ◽  
E Fathi ◽  
S Bagheri ◽  
...  
Keyword(s):  
Associated Factors ◽  
Antioxidant Status ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Significant Decline ◽  
Signaling Proteins ◽  
Bax Protein ◽  
Apoptosis And Inflammation

Background: Renal ischemia-reperfusion (IR) injury is one of the main leading causes of acute kidney injury associated with inflammation, oxidative stress and cell apoptosis. We studied the effects of prazosin, as a specific blocker of α1-AR, on renal IR injury. Methods: Rats were divided into normal control; untreated IR and prazosin-treated IR (1 mg/kg body weight). Prazosin was administered by intraperitoneal injection 30 min prior to IR induction. The level of urea/creatinine and oxidative factors were detected by colorimetric methods. Apoptosis-associated factors, inflammatory, and signaling proteins were analyzed in renal tissue. The abnormalities of renal histopathology were detected by immunohistochemistry. Results: Administration of prazosin to IR rats ameliorated serum urea and creatinine and IR-induced histopathological damages. Lipid peroxidation was significantly improved after treatment by prazosin in IR injury rats, however, antioxidant status was not affected. Rats subjected to IR injury activated Bax protein and NF-κB mediated inflammatory response. Moreover, treatment with prazosin inhibited renal NF-κB activation, resulting in a significant decline in pro-inflammatory cytokine of IL-6. Conclusion: These findings suggest that prazosin could be a good candidate to attenuate renal IR injury due to its ability to modulate renal function, apoptosis and inflammation.

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

2014 ◽  
Vol 306 (1) ◽  
pp. F75-F84 ◽  
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.

scholarly journals Fisetin attenuates Renal Ischemia/Reperfusion Injury by improving mitochondrial quality, reducing apoptosis and oxidative stress

2021 ◽  
Author(s):  
Priyanka N Prem ◽  
Gino A Kurian
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Cellular Level ◽  
Renal Protection ◽  
Mortality And Morbidity

Abstract Purpose Renal ischemic reperfusion (IR) injury is one of the major source of mortality and morbidity associated with acute kidney injury (AKI). Several flavonoids have shown to be renal protective against many nephrotoxic agents causing AKI. Fisetin, a promising flavonoid, is effective in the management of septic AKI, expected to ameliorate renal IR injury. Present study aim to generate evidence for fisetin mediated renal protection against IR injury Methodology: Male wistar rats of 200-250 g subjected to IR protocol by performing bilateral clamping for 45 minutes and reperfusion for 24 hours. Fisetin administrated 30 minutes ( 20 mg/kg b.wt, ip) before the surgery. Renal injury was evaluated by measuring the biomarkers in plasma, examining the ultrastructure of kidney and analyzing the apoptotic changes. Oxidative stress, antioxidant levels and mitochondrial function were analysed in the renal tissue. Results Fisetin administration significantly reduced the renal damages associated with IR, by improving estimated glomerular filtration rate (eGFR: IR-0.35 ml/min, F_IR-9.03 ml/min), reducing plasma creatinine level (IR-2.2 mg/dl, F_IR-0.92 mg/dl) and lowering urinary albumin/creatinine ratio (IR- 6.09 F_IR-2.16), caspase activity, decreased DNA fragmentation and reduced tubular injury score (IR- 11 F_IR-6.5). At cellular level, fisetin significantly reduced renal oxidative stress and augmented the antioxidant levels. Fisetin found to preserve mitochondrial electron transport chain activities and improved the ATP producing capacity in the renal tissue upon IR injury. Conclusion fisetin pre-treatment attenuate renal IR injury by improving the renal function, reducing the renal injury mediated by apoptosis, reducing free radical release, and augmenting mitochondrial function.

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

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1521
Author(s):  
John E. Brus ◽  
Daniel L. Quan ◽  
Kristin J. Wiley ◽  
Brittney Browning ◽  
Hannah Ter Haar ◽  
...  
Keyword(s):  
Animal Studies ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Chow Diet ◽  
Dependent Manner ◽  
Renal Hypertrophy ◽  
Expression Of Genes

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.

scholarly journals Effects of Nitroglycerine on Renal Ischemia-Reperfusion Injury in Adult Male Rats

Drug Research ◽  
2019 ◽  
Vol 69 (11) ◽  
pp. 612-620
Author(s):  
Fatemeh Ahmadi ◽  
Saeed Hajihashemi ◽  
Ali Rahbari ◽  
Fatemeh Ghanbari
Keyword(s):  
Lipid Peroxidation ◽  
Defense Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Blood Flow Rate ◽  
Renal Tissue ◽  
Male Rats ◽  
Control Group ◽  
Protective Effects

Abstract Background Ischemia-reperfusion (I-R) leads to acute kidney injury (AKI). The present study investigated the effects of nitroglycerine (NG) on improving renal dysfunctions caused by I-R in rats. Methodology Twenty-four rats were equally divided into four groups: (1) the control group, (2) the sham group, (3) the I-R group, and (4) NG-treated groups.NG (50 μg/kg) was injected intraperitoneally after induction of IR. I-R was induced through clamping of the bilateral renal artery and vein of both kidneys for 20 min followed by 24 h of reperfusion. Results NG significantly increased the creatinine clearance levels and renal blood flow rate (which was reduced by I-R). NG also significantly improved serum electrolytes (sodium and potassium) that were disordered by I-R. In addition, NG significantly offset impaired antioxidant defense mechanism and inhibited lipid peroxidation. Conclusions The results show NG has a protective effect on renal tissue against AKI caused by I-R. These protective effects mediated through antioxidant activity and decrease of lipid peroxidation.

scholarly journals Renal oxygenation in acute renal ischemia-reperfusion injury

2014 ◽  
Vol 306 (9) ◽  
pp. F1026-F1038 ◽  
Author(s):  
Amany Abdelkader ◽  
Julie Ho ◽  
Connie P. C. Ow ◽  
Gabriela A. Eppel ◽  
Niwanthi W. Rajapakse ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Tissue Hypoxia ◽  
Outer Medulla ◽  
Clinical Observations ◽  
Medullary Tissue ◽  
Cellular Hypoxia ◽  
Acute Renal Ischemia

Tissue hypoxia has been demonstrated, in both the renal cortex and medulla, during the acute phase of reperfusion after ischemia induced by occlusion of the aorta upstream from the kidney. However, there are also recent clinical observations indicating relatively well preserved oxygenation in the nonfunctional transplanted kidney. To test whether severe acute kidney injury can occur in the absence of widespread renal tissue hypoxia, we measured cortical and inner medullary tissue Po2 as well as total renal O2 delivery (Do2) and O2 consumption (V̇o2) during the first 2 h of reperfusion after 60 min of occlusion of the renal artery in anesthetized rats. To perform this experiment, we used a new method for measuring kidney Do2 and V̇o2 that relies on implantation of fluorescence optodes in the femoral artery and renal vein. We were unable to detect reductions in renal cortical or inner medullary tissue Po2 during reperfusion after ischemia localized to the kidney. This is likely explained by the observation that V̇o2 (−57%) was reduced by at least as much as Do2 (−45%), due to a large reduction in glomerular filtration (−94%). However, localized tissue hypoxia, as evidence by pimonidazole adduct immunohistochemistry, was detected in kidneys subjected to ischemia and reperfusion, particularly in, but not exclusive to, the outer medulla. Thus, cellular hypoxia, particularly in the outer medulla, may still be present during reperfusion even when reductions in tissue Po2 are not detected in the cortex or inner medulla.

scholarly journals Purinoceptors, Renal Microvascular Function and Hypertension

2020 ◽  
pp. 353-369
Author(s):  
Z GUAN ◽  
M MAKLED ◽  
E INSCHO
Keyword(s):  
Blood Flow ◽  
Kidney Function ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Microvascular Dysfunction ◽  
Microvascular Function ◽  
Renal Autoregulation ◽  
Electrolyte Homeostasis ◽  
Renal Microvasculature ◽  
Autoregulatory Mechanism

Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).

scholarly journals Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

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