Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury

2016 ◽  
Vol 43 (3) ◽  
pp. 195-205 ◽  
Author(s):  
Victoria Peer ◽  
Ramzia Abu Hamad ◽  
Sylvia Berman ◽  
Shai Efrati
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Treated Group ◽  
Renal Perfusion ◽  
Dnase I ◽  
Sprague Dawley ◽  
Contralateral Kidney ◽  
Debris Accumulation

Background: Massive DNA destruction/accumulation of cell-free DNA debris is a sensitive biomarker of progressive organ/tissue damage. Deleterious consequences of DNA debris accumulation are evident in cardiac ischemia, thrombosis, auto-inflammatory diseases, SLE-induced lupus nephritis and cystic fibrosis. In case of renal pathologies, degradation and elimination of DNA debris are suppressed, due to downregulated DNAse-I activity within the diseased kidneys. The aim of the current study was to evaluate whether exogenous DNAse-I administration might exert renoprotective effects in the setting of acute kidney injury (AKI or acute renal failure). Methods: Sprague-Dawley rats underwent unilateral nephrectomy, with simultaneous clamping of contralateral kidney artery. The treated group received DNAse-I injection before discontinuing anesthesia. Positive (ischemic) controls received saline injection. Negative (non-ischemic) controls were either non-operated or subjected to surgery of similar duress and duration without ischemia. Renal perfusion was evaluated using the Laser-Doppler technique. Blood was procured for evaluating DNAse-I activity, renal functioning, renal perfusion. The kidneys were allocated for histopathologic examinations and for the evaluation of renal hypoxia, intra-renal apoptosis and proliferation. Results: Contrary to the situation in untreated ischemic rats, renal perfusion was significantly improved in DNAse-treated animals, concomitantly with significant amelioration of damage to renal functioning and tissue integrity. Treatment with DNAse-I significantly decreased the ischemia-induced renal hypoxia and apoptosis, simultaneously stimulating renal cell proliferation. Exogenous DNAse-I administration accelerated the clearance of intra-renal apoptotic DNA debris. Conclusion: Functional/histologic hallmarks of renal injury were ameliorated, renal functioning improved, intra-renal hypoxia decreased and intra-renal regeneration processes were activated. Thus, DNAse-I treatment protected the kidney from deleterious consequences of ischemia-induced AKI.

scholarly journals P0558DICLOFENAC ENHANCES RENAL INFLAMMATION IN EXPERIMENTAL SUBCLINICAL ACUTE KIDNEY INJURY (AKI)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Johanna Störmer ◽  
Faikah Gueler ◽  
Song Rong ◽  
Mi-Sun Jang ◽  
Nelli Shushakova ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Tubular Atrophy ◽  
Renal Inflammation ◽  
Urine Production

Abstract Background and Aims Diclofenac is frequently used for pain control. In a previous study, we showed that already a single oral dose of diclofenac could reduce renal perfusion in healthy individuals. To investigate the influence of oral diclofenac administration on renal inflammation in the setting of pre-existing renal damage, we used a mouse model of subclinical acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) followed by diclofenac administration. Method Male CD1 mice (7-8 weeks old) underwent unilateral renal pedicle clamping for 15min to induce subclinical AKI. After reperfusion mice received a single oral dose of 100 or 200mg/kg diclofenac via oral gavage. Vehicle treated mice with unilateral IRI served as control. At day 1, mice were placed into metabolic cages to collect urine. Histology was performed on day 1 and 14 for renal morphology. Inflammation and fibrosis were investigated by immunohistochemistry and qPCR. Results Diclofenac treated mice showed reduced urine production. Morphologically, signs of AKI were more pronounced in diclofenac treated kidneys which also showed more Cox-2 positive tubuli in the cortex. On mRNA expression level the pro-inflammatory markers IL-6 and CXCL2, the chemoattractant for neutrophils, were elevated in the diclofenac group. Early upregulation of the pro-fibrotic markers CTGF and PAI-1 was detected already on d1 after IRI in the diclofenac group and tubular atrophy was pronounced after two weeks. Conclusion Already, a single oral dose of diclofenac causes aggravation of renal inflammation and progressive renal fibrosis in the setting of pre-existing subclinical acute kidney injury.

scholarly journals Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury

2011 ◽  
Vol 300 (3) ◽  
pp. F721-F733 ◽  
Author(s):  
David P. Basile ◽  
Jessica L. Friedrich ◽  
Jasmina Spahic ◽  
Nicole Knipe ◽  
Henry Mang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endothelial Cells ◽  
Fluorescent Protein ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Yellow Fluorescent Protein ◽  
Kidney Injury ◽  
Sprague Dawley ◽  
Mesenchymal Transition

Acute kidney injury induces the loss of renal microvessels, but the fate of endothelial cells and the mechanism of potential vascular endothelial growth factor (VEGF)-mediated protection is unknown. Cumulative cell proliferation was analyzed in the kidney of Sprague-Dawley rats following ischemia-reperfusion (I/R) injury by repetitive administration of BrdU (twice daily) and colocalization in endothelial cells with CD31 or cablin. Proliferating endothelial cells were undetectable for up to 2 days following I/R and accounted for only ∼1% of BrdU-positive cells after 7 days. VEGF-121 preserved vascular loss following I/R but did not affect proliferation of endothelial, perivascular cells or tubular cells. Endothelial mesenchymal transition states were identified by localizing endothelial markers (CD31, cablin, or infused tomato lectin) with the fibroblast marker S100A4. Such structures were prominent within 6 h and sustained for at least 7 days following I/R. A Tie-2-cre transgenic crossed with a yellow fluorescent protein (YFP) reporter mouse was used to trace the fate of endothelial cells and demonstrated interstititial expansion of YFP-positive cells colocalizing with S100A4 and smooth muscle actin following I/R. The interstitial expansion of YFP cells was attenuated by VEGF-121. Multiphoton imaging of transgenic mice revealed the alteration of YFP-positive vascular cells associated with blood vessels characterized by limited perfusion in vivo. Taken together, these data indicate that vascular dropout post-AKI results from endothelial phenotypic transition combined with an impaired regenerative capacity, which may contribute to progressive chronic kidney disease.

scholarly journals Diffusion Weighted Imaging and T2 Mapping Detect Inflammatory Response in the Renal Tissue during Ischemia Induced Acute Kidney Injury in Different Mouse Strains and Predict Renal Outcome

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1071
Author(s):  
Robert Greite ◽  
Katja Derlin ◽  
Dagmar Hartung ◽  
Rongjun Chen ◽  
Martin Meier ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Diffusion Weighted Imaging ◽  
T2 Mapping ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Outcome ◽  
Mouse Strains ◽  
Kidney Volume ◽  
Contralateral Kidney ◽  
Diffusion Weighted

To characterize ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI) in C57BL/6 (B6) and CD1-mice by longitudinal functional MRI-measurement of edema formation (T2-mapping) and inflammation (diffusion weighted imaging (DWI)). IRI was induced with unilateral right renal pedicle clamping for 35min. 7T-MRI was performed 1 and 14 days after surgery. DWI (7 b-values) and multiecho TSE sequences (7 TE) were acquired. Parameters were quantified in relation to the contralateral kidney on day 1 (d1). Renal MCP-1 and IL-6-levels were measured by qPCR and serum-CXCL13 by ELISA. Immunohistochemistry for fibronectin and collagen-4 was performed. T2-increase on d1 was higher in the renal cortex (127 ± 5% vs. 94 ± 6%, p < 0.01) and the outer stripe of the outer medulla (141 ± 9% vs. 111 ± 9%, p < 0.05) in CD1, indicating tissue edema. Medullary diffusivity was more restricted in CD1 than B6 (d1: 73 ± 3% vs. 90 ± 2%, p < 0.01 and d14: 77 ± 5% vs. 98 ± 3%, p < 0.01). Renal MCP-1 and IL-6-expression as well as systemic CXCL13-release were pronounced in CD1 on d1 after IRI. Renal fibrosis was detected in CD1 on d14. T2-increase and ADC-reduction on d1 correlated with kidney volume loss on d14 (r = 0.7, p < 0.05; r = 0.6, p < 0.05) and could serve as predictive markers. T2-mapping and DWI evidenced higher susceptibility to ischemic AKI in CD1 compared to B6.

scholarly journals MP240DEVELOPMENT OF AN “IN SITU” RENAL PERFUSION SYSTEM TO STUDY THE ORIGIN OF URINARY BIOMARKERS IN TWO ANIMAL MODELS OF ACUTE KIDNEY INJURY INDUCED BY GENTAMICIN AND ISCHEMIA-REPERFUSION

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii514-iii514
Author(s):  
Víctor Blanco-Gozalo ◽  
Laura Prieto-García ◽  
Sandra Sancho-Martínez ◽  
Yaremi Quiros-Luis ◽  
José López-Novoa ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Animal Models ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Urinary Biomarkers ◽  
Perfusion System

scholarly journals Targeting acute kidney injury in COVID-19

2020 ◽  
Vol 35 (10) ◽  
pp. 1652-1662 ◽  
Author(s):  
John A Kellum ◽  
J W Olivier van Till ◽  
George Mulligan
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Endothelial Damage ◽  
Acid Oxidation ◽  
Acid Base ◽  
The Impact ◽  
Pathophysiologic Mechanisms

Abstract As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in &gt;21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

scholarly journals Early antihypertensive treatment and ischemia-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F563-F570
Author(s):  
Robert Greite ◽  
Katja Derlin ◽  
Bennet Hensen ◽  
Anja Thorenz ◽  
Song Rong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Antihypertensive Treatment ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Renal Outcome ◽  
Major Surgery ◽  
Mesangial Matrix ◽  
Matrix Expansion

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.

Abstract 15477: Endothelial Cells Overexpressing Interleukin-8 Receptors are Renoprotective in Rats With Acute Kidney Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Fadi G Hage ◽  
Dongqi Xing ◽  
Samantha Giordano ◽  
Yuanyuan Guo ◽  
Suzanne Oparil ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endothelial Cells ◽  
Serum Creatinine ◽  
Ischemia Reperfusion ◽  
Femoral Vein ◽  
Kidney Injury ◽  
Capillary Density ◽  
Interleukin 8 ◽  
Left Renal Artery ◽  
Sprague Dawley

Introduction: In ischemia-reperfusion acute kidney injury (AKI) interleukin-8 (IL8) attracts neutrophils to the site of injury. Neutrophils interact with the damaged endothelium triggering the pro-inflammatory response that prolongs the underperfused state of the kidney and exacerbates injury. Hypothesis: We tested the hypothesis that intravenous transfusion of rat aortic endothelial cells (ECs) transduced with IL8 receptors (IL8RA/RB-ECs) ameliorates renal dysfunction and promotes structural recovery of the kidney post AKI. Methods and Results: Male Sprague-Dawley rats were subjected to sham surgery or AKI by clamping the left renal artery for 45 min and removing the right kidney. At time of reperfusion, 1.5x10 6 IL8RA/RB-ECs, ECs with empty adenoviral vector (AdNull-ECs), or vehicle were infused in the femoral vein. At 24 hrs after AKI, serum creatinine increased ~ 10 fold in the vehicle-treated group and then decreased towards baseline. IL8RA/RB-ECs but not AdNull-ECs significantly blunted the rise in serum creatinine (Fig) and decreased the local expression in the kidney and the circulating levels of inflammatory mediators at 24 hrs after AKI. At 6 wks after AKI, vehicle-treated rats had significant albuminuria compared to sham controls and EC treatment decreased albuminuria by ~65% (Fig). Stained kidney sections at 6 wks after AKI showed that vehicle-treated rats had increased interstitial collagen and decreased capillary density compared to sham controls. IL-8RA/RB-ECs were more effective at reducing interstitial collagen staining than AdNull-ECs. IL8RA/RB-ECs but not AdNull-ECs increased capillary density compared to vehicle (Fig). Conclusions: Following ischemia-reperfusion AKI, ECs equipped with IL8 receptors are attracted to the site of injury in order to inhibit inflammation, accelerate tissue repair, and preserve renal function. Our innovative cell-based strategy holds promise for improving outcomes after AKI.

scholarly journals P0557HYPERBARIC OXYGEN PRECONDITIONING INCREASES HEME OXYGENASE 1 EXPRESSION IN KIDNEY TISSUE AND IMPROVES KIDNEY FUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS WITH ISCHEMIC ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Milan Ivanov ◽  
Zoran Miloradovic ◽  
Nevena Mihailovic-Stanojevic ◽  
Djurdjica Jovovic ◽  
Danijela Karanovic ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Function ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Treated Group ◽  
Control Group ◽  
Heme Oxygenase 1 ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Abstract Background and Aims Renal ischemia–reperfusion (RIR) injury is one of the factors in the development of acute kidney injury (AKI). AKI is multifactorially caused, but the mechanism of pathogenesis and development of this disease is still incompletely defined. AKI is characterized by the sudden appearance, rapid progression of disease and very uncertain and often fatal outcome. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. HO-1 is now recognized as a protection factor in acute kidney injury. The aim of this study was to determine the effect of preconditioning with hyperbaric oxygen (HBO) on HO-1 expression in kidney tissue and kidney function in spontaneously hypertensive rats (SHR) during kidney ischemia–reperfusion injury. Method An experiment was performed in anesthetized, adult six-month-old male SHR. The right kidney was removed and the renal ischemia was performed by clamping the left renal artery for 40 minutes. SHR were randomly selected in three experimental groups: sham operated group (SHAM; n=7); AKI control group (AKI; n=9); and AKI group with HBO (AKI+HBO; n=9). Treated group were placed into experimental HBO chambers and exposed to pure oxygen, twice a day (in a 12 hour period, 8AM and 8 PM) for two consecutive days in the following manner: 10 minutes slow compression, 2.026 bar for 60 minutes, 10 minutes slow decompression. Mean arterial pressure (MAP) and HO-1 expression in kidney tissue were measured 24h after reperfusion. Clearance of creatinine (CCr), urea (CUr) and phosphate (CPh) were calculated 24h after reperfusion. Results After AKI induction reduction of blood pressure was recorded in both groups with AKI. Preconditioning with HBO significantly improved kidney function in rats with AKI compared to control group. HO-1 expression in kidney tissue was significantly higher in the treated group (p&lt;0,01) compared to SHAM and AKI control group. Conclusion Our results suggest that HBO treatment improves kidney function in the AKI+HBO vs. AKI control group. This implies that increased level of HO-1 due to preconditioning with hyperbaric oxygen may have beneficial effects on kidney function, and potentially protective effect in an ischemic model of AKI with hypertension.

scholarly journals Impaired Tubular Reabsorption Is the Main Mechanism Explaining Increases in Urinary NGAL Excretion Following Acute Kidney Injury in Rats

2020 ◽  
Vol 175 (1) ◽  
pp. 75-86 ◽  
Author(s):  
Sandra M Sancho-Martínez ◽  
Víctor Blanco-Gozalo ◽  
Yaremi Quiros ◽  
Laura Prieto-García ◽  
María J Montero-Gómez ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Tubular Reabsorption ◽  
Urinary Ngal ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Perfusion Studies ◽  
Glomerular Filtrate

Abstract Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted low-molecular weight iron-siderophore-binding protein. NGAL overexpression in injured tubular epithelia partly explains its utility as a sensitive and early urinary biomarker of acute kidney injury (AKI). Herein, we extend mechanistic insights into the source and kinetics of urinary NGAL excretion in experimental AKI. Three models of experimental AKI were undertaken in adult male Wistar rats; renal ischemia-reperfusion injury (IRI) and gentamicin (G) and cisplatin (Cisp) nephrotoxicity. Alongside standard histological and biochemical assessment of AKI, urinary NGAL excretion rate, plasma NGAL concentration, and renal NGAL mRNA/protein expression were assessed. In situ renal perfusion studies were undertaken to discriminate direct shedding of NGAL to the urine from addition of NGAL to the urine secondary to alterations in the tubular handling of glomerular filtrate-derived protein. Renal NGAL expression and urinary excretion increased in experimental AKI. In acute studies in both the IRI and G models, direct renal perfusion with Kreb’s buffer eliminated urinary NGAL excretion. Addition of exogenous NGAL to the Kreb’s buffer circuit, reestablishment of perfusion with systemic blood or reperfusion with renal vein effluent restored high levels of urinary NGAL excretion. Urinary NGAL excretion in AKI arises in large proportion from reduced reabsorption from the glomerular filtrate. Hence, subclinical cellular dysfunction could increase urinary NGAL, particularly in concert with elevations in circulating prerenal NGAL and/or pharmacological inhibition of tubular reabsorption. More granular interpretation of urinary NGAL measurements could optimize the scope of its clinical utility as a biomarker of AKI.

Sign in / Sign up

Export Citation Format

Share Document