p53-Mediated Oxidative Stress and Tubular Injury in Rats with Glycerol-Induced Acute Kidney Injury

Background: Some researches revealed that mitochondrial dysfunction is associated with various kidney injury. However, the role of mitochondrial dysfunction in the pathogenesis of acute kidney injury (AKI) still needs evidence. Methods: We evaluated the effect of mitochondrial complex I inhibitor rotenone on folic acid (FA)-induced AKI in mice. Results: Strikingly, the mice pretreated with rotenone at a dose of 200 ppm in food showed exacerbated kidney injury as shown by higher levels of blood urea nitrogen and creatinine compared with FA alone group. Meanwhile, both renal tubular injury score and the expression of renal tubular injury marker neutrophil gelatinase-associated lipocalin were further elevated in rotenone-pretreated mice, suggesting the deteriorated renal tubular injury. Moreover, the decrements of mitochondrial DNA copy number and the expressions of mitochondrial Cytochrome c oxidase subunit 1, mitochondrial NADH dehydrogenase subunit 1, and mitochondria-specific superoxide dismutase (SOD2) in the kidneys of FA-treated mice were further reduced in rotenone-pretreated mice, indicating the aggravated mitochondrial damage. In parallel with the SOD2 reduction, the oxidative stress markers of malondialdehyde and HO-1 displayed greater increment in AKI mice with rotenone pretreatment in line with the deteriorated apoptotic response and inflammation. Conclusion: Our results suggested that the inhibition of mitochondrial complex I activity aggravated renal tubular injury, mitochondrial damage, oxidative stress, cell apoptosis, and inflammation in FA-induced AKI.

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P0525ROLE OF NADPH OXIDASE 4 IN ACUTE KIDNEY INJURY ASSOCIATED TO MASSIVE INTRAVASCULAR HEMOLYSIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0525 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Cristina García Caballero ◽

Melania Guerrero Hue ◽

Alejandra Palomino Antolín ◽

Matilde Cabanillas ◽

Cristina Vazquez Carballo ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Renal Function ◽

Renal Damage ◽

Kidney Injury ◽

Tubular Injury ◽

Wild Type ◽

Intravascular Hemolysis ◽

Nadph Oxidase 4

Abstract Background and Aims Massive intravascular hemolysis is a common condition of several pathologies. It is associated with acute kidney injury (AKI) and progressive impairment of renal function. In this context, free hemoglobin (Hb) can exert harmful effects by accumulating in the kidney, where induces oxidative stress and it becomes cytotoxic. NADPH oxidase 4 (Nox4) is the principal source of reactive oxygen species (ROS) in the kidney. Nox4 is mostly expressed in proximal tubular cells with lower levels in glomerulus. The role of Nox4 in renal damage is not clear, with studies reporting beneficial or deleterious actions depending of the environmental conditions. For that reason we aimed to investigate the role of Nox4 in massive intravascular hemolysis-associated AKI. Method To study the role of Nox4 in AKI caused by massive intravascular hemolysis, we performed an experimental model of intravascular hemolysis by intraperitoneal injection of phenylhydrazine (200 mg/kg) in wild type (Nox4+/+) and Nox4 knockout mice (Nox4-/-). Mice were sacrificed 24 and 72 hours after intravascular hemolysis induction. We collected serum, urine and tissues sample. We analyzed renal function, oxidative stress, cell death and inflammation in these samples. In other experiments, wild type mice were treated with GKT137831 (10mg/kg/day), a potent Nox4 and Nox1 inhibitor, and mice were sacrificed 72h after induction of hemolysis. We also performed in vitro experiments in murine tubular epithelial cells (MCT) and murine podocytes cells to investigate the regulation of Nox4 in Hb-stimulated cells treated or not with GKT137831. Results Induction of intravascular hemolysis in Nox4+/+ mice increased creatinine and BUN levels and enhanced the expression of tubular injury markers, such as NGAL. These pathological effects were reduced in Nox4 knockout mice. Then, we analyzed oxidative stress in our experimental model thought determination of HO-1, ferritin, GSH and lipid peroxidation levels. All of these oxidative markers were reduced in Nox4-/- mice with intravascular hemolysis as compared with Nox4+/+ mice. We also observed that inflammatory markers such as IL-6, cell death and podocytes injury markers were reduced in Nox4-/- mice than in wild type mice, specially 72 hours after phenylhydrazine injection. In line with these results, GKT137831 administration ameliorated intravascular hemolysis-associated renal function impairment. Moreover, oxidative stress, tubular injury markers and podocyte injury were reduced in hemolytic mice treated with GKT137831. GKT137831 also reduced Hb- and heme-mediated oxidative stress in MCT and podocytes. Conclusion Our results show the important role of Nox4 in renal injury associated to massive intravascular hemolysis. Moreover, the inhibition of Nox4 may be a potential therapeutic target to prevent renal damage associated to Hb accumulation. These findings provide new insights into novel aspects of Hb-toxicity and may have important pathogenic and therapeutic implications for intravascular hemolysis related diseases

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N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00689.2012 ◽

2013 ◽

Vol 304 (12) ◽

pp. F1421-F1427 ◽

Cited By ~ 26

Author(s):

Kyle Ware ◽

Zahida Qamri ◽

Ayhan Ozcan ◽

Anjali A. Satoskar ◽

Gyongyi Nadasdy ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Iron Chelator ◽

Tubular Injury ◽

Model Treatment ◽

Experimental Group ◽

Group Serum ◽

Different Doses

Warfarin-related nephropathy (WRN) occurs under conditions of overanticoagulation with warfarin. WRN is characterized by glomerular hemorrhage with occlusive tubular red blood cell (RBC) casts and acute kidney injury (AKI). Herein we test the hypothesis that oxidative stress plays a role in the AKI of WRN. 5/6 Nephrectomy rats were treated with either warfarin (0.04 mg·kg−1·day−1) alone or with four different doses of the antioxidant N-acetylcysteine (NAC). Also tested was the ability of our NAC regimen to mitigate AKI in a standard ischemia-reperfusion model in the rat. Warfarin resulted in a threefold or greater increase in prothrombin time in each experimental group. Serum creatinine (Scr) increased progressively in animals receiving only warfarin + vehicle. However, in animals receiving warfarin + NAC, the increase in Scr was lessened, starting at 40 mg·kg−1·day−1 NAC, and completely prevented at 80 mg·kg−1·day−1 NAC. NAC did not decrease hematuria or obstructive RBC casts, but mitigated acute tubular injury. Oxidative stress in the kidney was increased in animals with WRN and it was decreased by NAC. The NAC regimen used in the WRN model preserved kidney function in the ischemia-reperfusion model. Treatment with deferoxamine (iron chelator) did not affect WRN. No iron was detected in tubular epithelial cells. In conclusion, this work taken together with our previous works in WRN shows that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The dominant mechanism of the AKI of WRN is tubular obstruction by RBC casts with increased oxidative stress in the kidney.

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

Open Life Sciences ◽

10.1515/biol-2021-0054 ◽

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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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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Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽

10.3390/biomedicines8120572 ◽

2020 ◽

Vol 8 (12) ◽

pp. 572

Author(s):

Jung-Yeon Kim ◽

Jungmin Jo ◽

Jaechan Leem ◽

Kwan-Kyu Park

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Renal Injury ◽

Manganese Superoxide Dismutase ◽

Immune Cell ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Kidney Injury ◽

Pleiotropic Effects ◽

Induced Apoptosis ◽

Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

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N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses

AJP Renal Physiology ◽

10.1152/ajprenal.00057.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. F956-F968 ◽

Cited By ~ 6

Author(s):

David M. Small ◽

Washington Y. Sanchez ◽

Sandrine F. Roy ◽

Christudas Morais ◽

Heddwen L. Brooks ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Mitochondrial Dysfunction ◽

Transforming Growth Factor ◽

Multiphoton Microscopy ◽

Kidney Injury ◽

Peroxisome Proliferator ◽

Fluorescence Lifetime Imaging ◽

Antioxidant Responses ◽

Acetyl Cysteine

Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice. NAC (5% in diet) was given to mice 7 days prior and up to 21 days post-IR (21d-IR). NAC treatment resulted in the following: prevented proximal tubular epithelial cell apoptosis at early IR (40-min postischemia), yet enhanced interstitial cell proliferation at 21d-IR; increased transforming growth factor-β1 expression independent of IR time; and significantly dampened nuclear factor-like 2-initiated cytoprotective signaling at early IR. In the long term, NAC enhanced cellular metabolic impairment demonstrated by increased peroxisome proliferator activator-γ serine-112 phosphorylation at 21d-IR. Intravital multiphoton microscopy revealed increased endogenous fluorescence of nicotinamide adenine dinucleotide (NADH) in cortical tubular epithelial cells during ischemia, and at 21d-IR that was not attenuated with NAC. Fluorescence lifetime imaging microscopy demonstrated persistent metabolic impairment by increased free/bound NADH in the cortex at 21d-IR that was enhanced by NAC. Increased mitochondrial dysfunction in remnant tubular cells was demonstrated at 21d-IR by tetramethylrhodamine methyl ester fluorimetry. In summary, NAC enhanced progression to CKD following AKI not only by dampening endogenous cellular antioxidant responses at time of injury but also by enhancing persistent kidney mitochondrial and metabolic dysfunction.

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Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32

Anesthesiology ◽

10.1097/aln.0000000000000448 ◽

2015 ◽

Vol 122 (1) ◽

pp. 72-86 ◽

Cited By ~ 38

Author(s):

Chenfang Luo ◽

Dongdong Yuan ◽

Xiaoyun Li ◽

Weifeng Yao ◽

Gangjian Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Transplantation ◽

Acute Kidney Injury ◽

Gap Junction ◽

Orthotopic Liver Transplantation ◽

Critical Role ◽

Kidney Injury ◽

Cellular Injury ◽

Knock Down ◽

Hypoxia Reoxygenation

Abstract Background: Postliver transplantation acute kidney injury (AKI) severely affects patient survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion induced enhancement of connexin32 (Cx32) gap junction plays a critical role in mediating postliver transplantation AKI and that pretreatment/precondition with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. Methods: Male Sprague–Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol (50 mg/kg) (n = 8 per group). Also, kidney tubular epithelial (NRK-52E) cells were subjected to hypoxia–reoxygenation and the function of Cx32 was manipulated by three distinct mechanisms: cell culture in different density; pretreatment with Cx32 inhibitors or enhancer; Cx32 gene knock-down (n = 4 to 5). Results: AOLT resulted in significant increases of renal Cx32 protein expression and gap junction, which were coincident with increases in oxidative stress and impairment in renal function and tissue injury as compared to sham group. Similarly, hypoxia–reoxygenation resulted in significant cellular injury manifested as reduced cell growth and increased lactate dehydrogenase release, which was significantly attenuated by Cx32 gene knock-down but exacerbated by Cx32 enhancement. Propofol inhibited Cx32 function and attenuated post-AOLT AKI. In NRK-52E cells, propofol reduced posthypoxic reactive oxygen species production and attenuated cellular injury, and the cellular protective effects of propofol were reinforced by Cx32 inhibition but cancelled by Cx32 enhancement. Conclusion: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.

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Comparison of Effects of Different Statins on Contrast-Induced Acute Kidney Injury in Rats: Histopathological and Biochemical Findings

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/6282486 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Xiao-lei Wang ◽

Tuo Zhang ◽

Liu-hua Hu ◽

Shi-qun Sun ◽

Wei-feng Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Lipid Lowering ◽

Control Group ◽

Sprague Dawley ◽

Atorvastatin Group ◽

New Strategy ◽

Ameliorative Effect ◽

Markers Of Oxidative Stress

Statins are a promising new strategy to prevent contrast-induced acute kidney injury (CI-AKI). In this study we compared the ameliorative effect of different statins in a rat model of CI-AKI. Sprague-Dawley rats were divided into five groups: control group; CI-AKI group; CI-AKI + rosuvastatin group (10 mg/kg/day); CI-AKI + simvastatin group (80 mg/kg/day); and CI-AKI + atorvastatin group (20 mg/kg/day). CI-AKI was induced by dehydration for 72 hours, followed by furosemide intramuscular injection 20 minutes before low-osmolar contrast media (CM) intravenous injection. Statins were administered by oral gavage once daily for 3 consecutive days before CM injection and once 4 hours after CM injection. Rats were sacrificed 24 hours after CM injection, and renal function, kidney histopathology, nitric oxide (NO) metabolites, and markers of oxidative stress, inflammation, and apoptosis were evaluated. The results showed that atorvastatin and rosuvastatin but not simvastatin ameliorated CM-induced serum creatinine elevation and histopathological alterations. Atorvastatin and rosuvastatin showed similar effectiveness against CM-induced oxidative stress, but simvastatin was less effective. Atorvastatin was most effective against NO system dysfunction and cell apoptosis, whereas rosuvastatin was most effective against inflammation. Our findings indicate that statins exhibit differential effects in preventing CI-AKI when given at equivalent lipid-lowering doses.

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Immunohistochemical Analysis of 4-HNE, NGAL, and HO-1 Tissue Expression after Apocynin Treatment and HBO Preconditioning in Postischemic Acute Kidney Injury Induced in Spontaneously Hypertensive Rats

Antioxidants ◽

10.3390/antiox10081163 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1163

Author(s):

Sanjin Kovacevic ◽

Milan Ivanov ◽

Maja Zivotic ◽

Predrag Brkic ◽

Zoran Miloradovic ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Spontaneously Hypertensive Rats ◽

Kidney Injury ◽

Immunohistochemical Analysis ◽

Tissue Expression ◽

Pure Oxygen ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Renal Expression

Oxidative stress has been considered as a central aggravating factor in the development of postischemic acute kidney injury (AKI). The aim of this study was to perform the immunohistochemical analysis of 4-hydroxynonenal (4-HNE), neutrophil gelatinase-associated lipocalin (NGAL), and heme oxygenase-1 (HO-1) tissue expression after apocynin (APO) treatment and hyperbaric oxygenation (HBO) preconditioning, applied as single or combined protocol, in postischemic acute kidney injury induced in spontaneously hypertensive rats (SHR). Twenty-four hours before AKI induction, HBO preconditioning was carried out by exposing to pure oxygen (2.026 bar) twice a day, for 60 min in two consecutive days. Acute kidney injury was induced by removal of the right kidney while the left renal artery was occluded for 45 min by atraumatic clamp. Apocynin was applied in a dose of 40 mg/kg body weight, intravenously, 5 min before reperfusion. We showed increased 4-HNE renal expression in postischemic AKI compared to Sham-operated (SHAM) group. Apocynin treatment, with or without HBO preconditioning, improved creatinine and phosphate clearances, in postischemic AKI. This improvement in renal function was accompanied with decreased 4-HNE, while HO-1 kidney expression restored close to the control group level. NGAL renal expression was also decreased after apocynin treatment, and HBO preconditioning, with or without APO treatment. Considering our results, we can say that 4-HNE tissue expression can be used as a marker of oxidative stress in postischemic AKI. On the other hand, apocynin treatment and HBO preconditioning reduced oxidative damage, and this protective effect might be expected even in experimental hypertensive condition.

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