Preactivation of AMPK by metformin may ameliorate the epithelial cell damage caused by renal ischemia

Alterations in epithelial cell polarity and in the subcellular distributions of epithelial ion transport proteins are key molecular consequences of acute kidney injury and intracellular energy depletion. AMP-activated protein kinase (AMPK), a cellular energy sensor, is rapidly activated in response to renal ischemia, and we demonstrate that its activity is upregulated by energy depletion in Madin-Darby canine kidney (MDCK) cells. We hypothesized that AMPK activity may influence the maintenance or recovery of epithelial cell organization in mammalian renal epithelial cells subjected to energy depletion. MDCK cells were ATP depleted through a 1-h incubation with antimycin A and 2-deoxyglucose. Immunofluoresence localization demonstrated that this regimen induces mislocalization of the Na-K-ATPase from its normal residence at the basolateral plasma membrane to intracellular vesicular compartments. When cells were pretreated with the AMPK activator metformin before energy depletion, basolateral localization of Na-K-ATPase was preserved. In MDCK cells in which AMPK expression was stably knocked down with short hairpin RNA, preactivation of AMPK with metformin did not prevent Na-K-ATPase redistribution in response to energy depletion. In vivo studies demonstrate that metformin activated renal AMPK and that treatment with metformin before renal ischemia preserved cellular integrity, preserved Na-K-ATPase localization, and led to reduced levels of neutrophil gelatinase-associated lipocalin, a biomarker of tubular injury. Thus AMPK may play a role in preserving the functional integrity of epithelial plasma membrane domains in the face of energy depletion. Furthermore, pretreatment with an AMPK activator before ischemia may attenuate the severity of renal tubular injury in the context of acute kidney injury.

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7-Hydroxycoumarin Protects Against Cisplatin-Induced Acute Kidney Injury by Inhibiting RIPK1/RIPK3/MLKL-Mediated Necroptosis and Promoting Sox-9-Mediated Tubular Epithelial Cell Proliferation

SSRN Electronic Journal ◽

10.2139/ssrn.3397177 ◽

2019 ◽

Author(s):

Wei-Feng Wu ◽

Jia-Nan Wang ◽

Zeng Li ◽

Biao Wei ◽

Juan Jin ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Kidney Injury ◽

Epithelial Cell ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Epithelial Cell Proliferation

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Post-treatment with JP-1302 protects against renal ischemia/reperfusion-induced acute kidney injury in rats

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2018.12.008 ◽

2019 ◽

Vol 139 (3) ◽

pp. 137-142 ◽

Cited By ~ 5

Author(s):

Takaomi Shimokawa ◽

Hidenobu Tsutsui ◽

Takeshi Miura ◽

Masashi Takama ◽

Kohei Hayashi ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Post Treatment ◽

Renal Ischemia

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Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection

BMC Nephrology ◽

10.1186/s12882-020-02213-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Katarzyna Szajek ◽

Marie-Elisabeth Kajdi ◽

Valerie A. Luyckx ◽

Thomas Hans Fehr ◽

Ariana Gaspert ◽

...

Keyword(s):

Acute Kidney Injury ◽

Interstitial Nephritis ◽

Kidney Biopsy ◽

Kidney Diseases ◽

Case Reports ◽

Kidney Injury ◽

Maculopapular Rash ◽

Tubular Injury ◽

Granulomatous Interstitial Nephritis ◽

First Case

Abstract Background Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 – associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive. Case Presentation The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis. Conclusions Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.

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The impact of fluid status and decremental PEEP strategy on cardiac function and lung and kidney damage in mild-moderate experimental acute respiratory distress syndrome

Respiratory Research ◽

10.1186/s12931-021-01811-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Nazareth N. Rocha ◽

Cynthia S. Samary ◽

Mariana A. Antunes ◽

Milena V. Oliveira ◽

Matheus R. Hemerly ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Epithelial Cell ◽

Distress Syndrome ◽

Cell Damage ◽

Kidney Injury ◽

Fluid Administration ◽

Kidney Damage ◽

Fluid Status ◽

Pulmonary Arterial ◽

Lung And Kidney

Abstract Background We evaluated the effects of abrupt versus gradual PEEP decrease, combined with standard versus high-volume fluid administration, on cardiac function, as well as lung and kidney damage in an established model of mild-moderate acute respiratory distress syndrome (ARDS). Methods Wistar rats received endotoxin intratracheally. After 24 h, they were treated with Ringer’s lactate at standard (10 mL/kg/h) or high (30 mL/kg/h) dose. For 30 min, all animals were mechanically ventilated with tidal volume = 6 mL/kg and PEEP = 9 cmH2O (to keep alveoli open), then randomized to undergo abrupt or gradual (0.2 cmH2O/min for 30 min) PEEP decrease from 9 to 3 cmH2O. Animals were then further ventilated for 10 min at PEEP = 3 cmH2O, euthanized, and their lungs and kidneys removed for molecular biology analysis. Results At the end of the experiment, left and right ventricular end-diastolic areas were greater in animals treated with high compared to standard fluid administration, regardless of PEEP decrease rate. However, pulmonary arterial pressure, indicated by the pulmonary acceleration time (PAT)/pulmonary ejection time (PET) ratio, was higher in abrupt compared to gradual PEEP decrease, independent of fluid status. Animals treated with high fluids and abrupt PEEP decrease exhibited greater diffuse alveolar damage and higher expression of interleukin-6 (a pro-inflammatory marker) and vascular endothelial growth factor (a marker of endothelial cell damage) compared to the other groups. The combination of standard fluid administration and gradual PEEP decrease increased zonula occludens-1 expression, suggesting epithelial cell preservation. Expression of club cell-16 protein, an alveolar epithelial cell damage marker, was higher in abrupt compared to gradual PEEP decrease groups, regardless of fluid status. Acute kidney injury score and gene expression of kidney injury molecule-1 were higher in the high versus standard fluid administration groups, regardless of PEEP decrease rate. Conclusion In the ARDS model used herein, decreasing PEEP abruptly increased pulmonary arterial hypertension, independent of fluid status. The combination of abrupt PEEP decrease and high fluid administration led to greater lung and kidney damage. This information adds to the growing body of evidence that supports gradual transitioning of ventilatory patterns and warrants directing additional investigative effort into vascular and deflation issues that impact lung protection.

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MO328ASYMPTOMATIC HYPERURICEMIA ACTS AS ANTIOXIDANT DURING ACUTE KIDNEY INJURY AND DISEASE*

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab084.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Qiuyue Ma ◽

Viviane Gnemmi ◽

Anders Hans-Joachim ◽

Stefanie Steiger

Keyword(s):

Acute Kidney Injury ◽

Fatty Acid ◽

Epithelial Cells ◽

Kidney Function ◽

Metabolic Activity ◽

Mitochondrial Biogenesis ◽

Kidney Injury ◽

Acid Oxidation ◽

Tubular Epithelial Cells ◽

Tubular Injury

Abstract Background and Aims Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells. Method Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry. Results We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right). Conclusion Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.

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Tubular injury and cell-cycle arrest biomarkers to predict acute kidney injury in noncritically ill children receiving aminoglycosides

Biomarkers in Medicine ◽

10.2217/bmm-2019-0419 ◽

2020 ◽

Vol 14 (10) ◽

pp. 879-894

Author(s):

Hayton Chui ◽

Jillian Caldwell ◽

Mariya Yordanova ◽

Vedran Cockovski ◽

Daniel Fredric ◽

...

Keyword(s):

Cell Cycle ◽

Acute Kidney Injury ◽

Febrile Neutropenia ◽

Prospective Study ◽

Area Under The Curve ◽

Kidney Injury ◽

Tubular Injury ◽

Early Biomarkers ◽

Cycle Arrest ◽

A Prospective Study

Aim: NGAL, IL-18, KIM-1 as well as urinary TIMP2 and IGFBP7 and their mathematical product (TIMP2*IGFBP7) were evaluated for detecting pediatric aminoglycoside acute kidney injury (AG-AKI). Methods: In a prospective study, noncritically ill children received aminoglycosides (AG) ≥3 days. The area under the curve (AUC) for biomarkers to detect AKI was calculated by a) days before AKI onset; b) treatment days. Results: There were 113 AG episodes (68% febrile neutropenia). The AKI group had a higher proportion with febrile neutropenia. The AKI group had significantly lower NGAL 3 days before AKI, as patients with febrile neutropenia had a lower NGAL during AG treatment (p < 0.05). NGAL, IL-18 and TIMP2*IGFBP7 had AUC ≥0.73 at 3, 2 and 2 days before AKI onset. Conclusion: NGAL, IL-18 and TIMP2*IGFBP7 were modest early biomarkers of AG-AKI. Febrile neutropenia was associated with lower NGAL.

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Urinary N-Acetyl-Beta-D-Glucosaminidase Activity in Rat Experimental Ischemic and Toxic Models of Acute Kidney Injury

Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca Veterinary Medicine ◽

10.15835/buasvmcn-vm:12618 ◽

2017 ◽

Vol 74 (1) ◽

pp. 105

Author(s):

Razvan Andrei CODEA ◽

Mircea MIRCEAN ◽

Sidonia Alina BOGDAN ◽

Andras Laszlo NAGY ◽

Alexandra BIRIS ◽

...

Keyword(s):

Acute Kidney Injury ◽

Experimental Model ◽

Wistar Rats ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Control Group ◽

Tubular Injury ◽

Group 2 ◽

Group 1

The identification of a suitable prevention method which facilitates limiting the deleterious effects of acute kidney injuries is highly required. In order to identify a proper treatment for acute kidney injuries, a suitable experimental model that replicates the structural, metabolic and inflammatory lesions that occur in the natural acute injured kidney is highly necessary. Intense urinary NAG activity can be found in a variety of renal disease such as toxic nephropathies, ischemic renal injury following cardiac surgery or renal transplantation but also in glomerular disease especially in diabetic nephropathy. Rises in urinary NAG enzyme activity strongly suggests tubular cell damage and support NAG enzyme as a biomarker of renal tubular injury. The aim of this paper is to obtain a stable in vivo acute kidney injury experimental model, in Wistar, rats and to evaluate the urinary activity of N-acetyl-Î²-D-glucosaminidase (NAG) enzyme, blood levels of urea and creatinine and microstructural renal alterations induced by ischemia/reperfusion injury respectively gentamicin nephrotoxicity. For this purpose we have used a rat experimental model. Adult male Wistar rats weighing 250-300 g were randomly divided into 3 groups with 8 rats in each group. Group 1 served as a model for the renal ischemia/reperfusion injury experiment, group 2 served for toxic kidney injury experimental model and group 3 served as control group. All individuals in both groups 1 and 2 presented marked elevations in blood urea and creatinine at the moment of euthanasia (day 3 for group 1 and day 9 for group 2) compared to the control group where biochemical values remained within normal limits. Urine analysis of both group 1 and 2 showed marked urinary NAG index activity which suggests acute tubular injury, suggestion confirmed by histological evaluation of the renal parenchyma sampled from this subjects

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Characterization of the Oxidative Stress in Renal Ischemia/Reperfusion-Induced Cardiorenal Syndrome Type 3

BioMed Research International ◽

10.1155/2020/1605358 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Wellington Caio-Silva ◽

Danielle da Silva Dias ◽

Carolina Victoria Cruz Junho ◽

Karine Panico ◽

Raquel Silva Neres-Santos ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Damage ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cardiorenal Syndrome ◽

Redox Balance ◽

Renal Ischemia ◽

Cellular Damage ◽

Cellular Mechanisms ◽

Inflammatory Conditions

In kidney disease (KD), several factors released into the bloodstream can induce a series of changes in the heart, leading to a wide variety of clinical situations called cardiorenal syndrome (CRS). Reactive oxygen species (ROS) play an important role in the signaling and progression of systemic inflammatory conditions, as observed in KD. The aim of the present study was to characterize the redox balance in renal ischemia/reperfusion-induced cardiac remodeling. C57BL/6 male mice were subjected to occlusion of the left renal pedicle, unilateral, for 60 min, followed by reperfusion for 8 and 15 days, respectively. The following redox balance components were evaluated: catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (FRAP), NADPH oxidase (NOX), nitric oxide synthase (NOS), hydrogen peroxide (H2O2), and the tissue bioavailability of nitric oxide (NO) such as S-nitrosothiol (RSNO) and nitrite (NO2−). The results indicated a process of renoprotection in both kidneys, indicated by the reduction of cellular damage and some oxidant agents. We also observed an increase in the activity of antioxidant enzymes, such as SOD, and an increase in NO bioavailability. In the heart, we noticed an increase in the activity of NOX and NOS, together with increased cell damage on day 8, followed by a reduction in protein damage on day 15. The present study concludes that the kidneys and heart undergo distinct processes of damage and repair at the analyzed times, since the heart is a secondary target of ischemic kidney injury. These results are important for a better understanding of the cellular mechanisms involved in CRS.

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Diagnostic Utility of Serial Microscopic Examination of the Urinary Sediment in Acute Kidney Injury

Kidney360 ◽

10.34067/kid.0004022020 ◽

2020 ◽

pp. 10.34067/KID.0004022020

Author(s):

Vipin Varghese ◽

Maria Soledad Rivera ◽

Ali A. Alalwan ◽

Ayman M. Alghamdi ◽

Manuel E. Gonzalez ◽

...

Keyword(s):

Acute Kidney Injury ◽

Serum Creatinine ◽

Microscopic Examination ◽

Odds Ratio ◽

Positive Likelihood Ratio ◽

Kidney Injury ◽

Diagnostic Utility ◽

Tubular Injury ◽

Urinary Sediment ◽

Unclear Etiology

Background. Microscopic examination of the urinary sediment (MicrExUrSed) is an established diagnostic tool for acute kidney injury (AKI). Single inspection of urine during the course of AKI is a mere snapshot affected by timing. We hypothesized that longitudinal MicrExUrSed provides information not identified in a single inspection. Methods. MicrExUrSed was undertaken in patients with AKI stage >= 2 and suspected intrinsic cause of AKI seen for nephrology consultation over a 2-year period. MicrExUrSed was performed on the day of consultation and repeated at a second (2 - 3 days later) and/or third (4 - 10 days later) interval. Cast scores were assigned to each specimen. Chawla scores (CS) 3 to 4 and Perazella scores (PS) 2 to 4 were categorized as consistent with acute tubular injury (ATI), whereas CS 1 to 2 and PS 0 to 1 were categorized as non-diagnostic for ATI (non-ATI). Non-recovering AKI was defined as a rise in serum creatinine (sCr) ≥ 0.1 mg/dL between microscopy intervals. Results. At least 2 consecutive MicrExUrSed were performed in 121 patients [46% women, mean age 61 ± 14, mean sCr at consult of 3.3 +/- 1.9 mg/dL]. On day 1, a CS and PS consistent with non-ATI was assigned to 64 (53%) and 70 (58%) patients, respectively. After a subsequent MicrExUrSed, CS and PS changed to ATI in 14 (22%) and 16 (23%) patients. Thus, 20 - 24% of patients only revealed evidence of ATI after serial MicrExUrSed was performed. Patients with non-recovering AKI were more likely to change their PS to ATI category [odds ratio: 5.8 (CI:1.7-19.3; p=0.005) and positive likelihood ratio: 2.0 (CI: 1.3-2.9)]. Conclusion. Serial MicrExUrSed revealed diagnostic findings of ATI not identified in a single examination. A repeat MicrExUrSed may be warranted in cases of AKI of unclear etiology or not recovering.

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