8-hydroxy-2--deoxyguanosine and Acute-Kidney-Injury

Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia.. The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers.. After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period.. These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aged; Arginine; Atherosclerosis; Biomarkers; Cardiovascular System; Carotid Intima-Media Thickness; Deoxyguanosine; Dose-Response Relationship, Drug; Erythropoietin; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prospective Studies; Recombinant Proteins; Treatment Outcome

To investigate well-controlled congenital hypothyroidism on the markers associated with early kidney injury and oxidative DNA damage.. Twenty-three children with euthyroid congenital hypothyroidism aged 3-6 years and 19 age- and gender-matched controls were enrolled. Serum levels of albumin, C-reactive protein, cysteine C, globulin, pre-albumin, and total protein were detected. Urine levels of albumin, fibrin degradation products, IgG, β2-microglobulin, and 8-hydroxydeoxyguanosine (8-OHdG) were also measured. Clinical and biochemical characteristics were evaluated between the two groups.. Serum levels of C-reactive protein were higher, but pre-albumin was lower in patients with congenital hyperthyroidism compared with the controls (all p<0.001). Urinary levels of IgG were higher in patients with congenital hyperthyroidism than in the controls (p=0.011). However, urinary levels of albumin excretion and 8-OHdG were similar to those in the controls. Serum pre-albumin levels were negatively correlated with urinary 8-OHdG levels (r=-0.479, p=0.016) in patients with congenital hypothyroidism.. It is concluded that inflammatory and oxidative markers were slightly altered in well-controlled congenital hypothyroidism. The levels of urinary 8-OHdG and albumin excretion were not significantly different.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Biomarkers; C-Reactive Protein; Case-Control Studies; Child, Preschool; Congenital Hypothyroidism; Deoxyguanosine; Female; Follow-Up Studies; Humans; Inflammation; Inflammation Mediators; Male; Oxidative Stress; Prognosis

Ischemia-reperfusion injury (IRI) has been considered as the major cause of acute kidney injury and can result in poor long-term graft function. Functional recovery after IRI is impaired in the elderly. In the present study, we aimed to compare kidney morphology, function, oxidative stress, inflammation, and development of renal fibrosis in young and aged rats after renal IRI.. Rat models of warm renal IRI were established by clamping left pedicles for 45 min after right nephrectomy, then the clamp was removed, and kidneys were reperfused for up to 12 wk. Biochemical and histologic renal damage were assessed at 12 wk after reperfusion. The immunohistochemical staining of monocyte macrophage antigen-1 (ED-1) and transforming growth factor beta 1 (TGF-β1) and messenger RNA level of TGF-β1 in the kidney were analyzed.. Renal IRI caused significant increases of malondialdehyde and 8-hydroxydeoxyguanosine levels and a decrease of superoxide dismutase activity in young and aged IRI rats; however, these changes were more obvious in the aged rats. IRI resulted in severe inflammation and tubulointerstitial fibrosis with decreased creatinine (Cr) clearance and increased histologic damage in aged rats compared with young rats. Moreover, we measured the ratio of Cr clearance between young and aged IRI rats. It demonstrated that aged IRI rats did have poor Cr clearance compared with the young IRI rats. ED-1 and TGF-β1 expression levels in the kidney were significantly higher in aged rats than in young rats after IRI.. Aged rats are more susceptible to IRI-induced renal failure, which may associate with the increased oxidative stress, increased histologic damage, and increased inflammation and tubulointerstitial fibrosis. Targeting oxidative stress and inflammatory response should improve the kidney recovery after IRI.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Age Factors; Aging; Animals; Deoxyguanosine; Disease Models, Animal; Fibrosis; Inflammation; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Severity of Illness Index; Time

Oxidative stress has been implicated to contribute to HIV-induced kidney cell injury; however, the role of p53, a modulator of oxidative stress, has not been evaluated in the development of HIV-associated nephropathy (HIVAN). We hypothesized that mammalian target of rapamycin (mTOR) may be critical for the induction of p53-mediated oxidative kidney cell injury in HIVAN. To test our hypothesis, we evaluated the effect of an mTOR inhibitor, rapamycin, on kidney cell p53 expression, downstream signaling, and kidney cell injury in both in vivo and in vitro studies. Inhibition of the mTOR pathway resulted in downregulation of renal tissue p53 expression, associated downstream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, and apoptosed and 8-hydroxy deoxyguanosine (8-OHdG)-positive (+ve) cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated the redox-sensitive stress response program in the form of enhanced expression of manganese superoxide dismutase (MnSOD) and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition downregulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed a lack of expression of p53 as well as attenuated podocyte apoptosis, this suggests that mTOR is critical for kidney cell p53 activation and associated oxidative kidney cell injury in the HIV milieu.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; AIDS-Associated Nephropathy; Animals; Apoptosis; Catalase; Deoxyguanosine; Gene Silencing; HIV Infections; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Oxidative Stress; Podocytes; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Superoxide Dismutase; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

The incidence of acute kidney injury (AKI) in the elderly population has steadily increased in recent years. Functional recovery after AKI is also impaired in the elderly; however, the mechanism underlying these age-related differences is not well understood. In the present study, we assessed kidney morphology, function, and oxidative stress in young and aged rats after renal ischemia and reperfusion.. Young (6- to 7-wk-old) and aged (60- to 65-wk-old) male Wistar rats were divided into four groups based on age and treatment: renal ischemia-reperfusion in young rats (young IR); renal ischemia-reperfusion in aged rats (aged IR); sham treatment in young rats (young control), and sham treatment in aged rats (aged control). Rats were sacrificed 24 h after treatment, serum blood urea nitrogen (BUN) and creatinine (Cre) concentrations were determined, and kidney tissue histology and 8-hydroxydeoxyguanosine (8-OHdG) levels were evaluated.. After ischemia-reperfusion, serum BUN, and Cre levels were higher in aged rats than in young rats. Reperfusion-induced kidney damage and kidney tissue 8-OHdG levels were also more severe in the aged IR group. Moreover, plasma antioxidant potential was lower in aged IR rats than in young IR rats.. Aged rats exhibited reduced antioxidant potential and increased oxidative stress after ischemia-reperfusion. Our findings demonstrate that aged rats experience more severe reperfusion-induced injuries compared with young rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aging; Animals; Blood Urea Nitrogen; Creatinine; Deoxyguanosine; Kidney; Male; Models, Animal; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury

Acute kidney injury (AKI) is common in the intensive care unit, and one of its primary causes is renal ischemia-reperfusion (I/R) injury. Human atrial natriuretic peptide (hANP) exerts various pharmacologic effects, including renal protection. In the present study, we evaluated the renal protective effect of hANP in a rat model of renal I/R.. Male Wistar rats were divided into three groups that received the following treatments: induction of renal I/R (I/R group); continuous intravenous injection of hANP followed 30 min later by induction of renal I/R (hANP+I/R group); and sham treatment (control group). Rats were sacrificed after 60 min of ischemia and 24 h of reperfusion or sham treatment. To evaluate the renal protective effects if hANP, serum blood urea nitrogen (BUN) and creatinine (Cre) concentrations were determined, kidneys were histologically assessed, and serum biomarkers of oxidative stress were evaluated. In addition, antimycin A (AMA)-stimulated RAW264.7 cells were treated with hANP to assess its antioxidant effects.. Serum BUN and Cre levels were elevated in the I/R group; however, these increases were significantly inhibited in the hANP + I/R group. Similarly, kidney tissue damage observed in the I/R group was attenuated in the hANP + I/R group. In vitro, AMA-stimulated cells treated with hANP showed reduced reactive oxygen species activity compared to cells treated with AMA alone.. Our findings indicate that hANP may be effective in the treatment of various types of I/R injuries.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Biomarkers; Blood Urea Nitrogen; Cell Line; Deoxyguanosine; Humans; Hydroxyl Radical; Kidney; Male; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury

Cirrhosis increases the risk of kidney injury and sepsis, leading to increased mortality. Elevated levels of plasma asymmetric dimethylarginine (ADMA) occur in patients critically ill with cirrhosis, renal failure, and sepsis. We used a rat model of cirrhosis with superimposed sepsis to assess the relationship of plasma and tissue ADMA profiles with acute kidney injury and survival. Seventeen-day-old male Sprague-Dawley rats (n = 37) were randomly assigned to four groups: (1) sham operation plus diet control (n = 6); (2) bile duct ligation (BDL, n = 8); (3) sham operation plus lipopolysaccharide (LPS, n = 9); and (4) BDL plus LPS (n = 14). Lipopolysaccharide was given by intraperitoneal injection (1 mg/kg in saline) 3 h before sacrifice. All rats were sacrificed 14 days after surgery. Lipopolysaccharide increased the rate of BDL-associated death and dysfunction of the liver and kidneys. These results were supported by increased levels of plasma ADMA and a decreased L-arginine/ADMA ratio (AAR). Plasma and tissue levels of ADMA and AAR were not correlated. Lipopolysaccharide restored BDL-induced ADMA level elevation in the liver but increased ADMA level in the kidneys. Lipopolysaccharide increased hepatic AAR, decreased renal AAR, and paradoxically mediated the expression of neuronal nitric oxide synthase-β in the liver and kidneys. A novel mechanism underlies the LPS-mediated L-arginine-ADMA-nitric oxide pathway activation and exacerbation of kidney injury and mortality in our BDL model. In the presence of cirrhosis with superimposed sepsis, simultaneous lowering of ADMA levels and enhancement of L-arginine levels to restore plasma and renal AARs may be an optimal strategy for the treatment of kidney injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Animals; Arginine; Bile Ducts; Blotting, Western; Chromatography, High Pressure Liquid; Citrulline; Deoxyguanosine; Endotoxemia; Immunohistochemistry; Male; Rats; Rats, Sprague-Dawley

Paraquat (PQ)-induced acute kidney injury (AKI) might show the role for reactive oxygen species (ROS) in AKI. The purpose of this study was to investigate the characteristics of early urinary biomarkers in patients with acute PQ poisoning. We prospectively investigated changes in urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in acute PQ intoxication.. From May 2008 to September 2008, 20 patients were included. Urine KIM-1, NGAL, and 8-hydroxy-2-deoxyguanosine (8-OH-dG) were measured at 6, 12, 24, 48, 72, and 120 h after ingestion. The serum creatinine was measured also at the same intervals.. AKI was diagnosed in 11 out of 20 patients. There was a significant difference in the creatinine at 12 h between patients with AKI and those without AKI (0.50 +/- 0.15 vs. 1.04 +/- 0.53 mg/dL, p = 0.01). Urinary NGAL was higher in patients with AKI compared to patients without AKI at 24 h (2.84 vs. 0.96 ng/mL). Urinary KIM-1 was not different in comparisons between patients with AKI and those without AKI. Regardless of the AKI, the NGAL and KIM-1 were increased at between 24 and 48 h.. PQ is a very potent stimulant of NGAL-1 and KIM-1. Therefore, the NGAL might reflect reactive oxygen species-induced kidney injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Acute-Phase Proteins; Adult; Aged; Biomarkers; Creatinine; Deoxyguanosine; Female; Hepatitis A Virus Cellular Receptor 1; Herbicides; Humans; Lipocalin-2; Lipocalins; Male; Membrane Glycoproteins; Middle Aged; Paraquat; Prospective Studies; Proto-Oncogene Proteins; Reactive Oxygen Species; Receptors, Virus; Time Factors

Establishment of non-invasive urinary biomarkers for the prediction of acute renal failure (ARF) is important. We evaluated whether urinary oxidative stress markers reflect intrarenal oxidative stress in cisplatin (CDDP)-induced ARF, and whether these markers can be used for the prediction of future ARF.. Urinary malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured up to day 14 post-CDDP (6 mg/kg) injection in rats. MDA and 8-OHdG expressions were examined in kidneys.. CDDP induced an increase in serum creatinine (Scr), blood urea nitrogen (BUN), and tubular damage at day 5, increased urinary MDA excretion and MDA expression in kidneys at day 1 (but returned to basal values by day 3), increased urinary excretion of 8-OHdG at day 5 till day 14 (though the number of 8-OHdG-positive tubular cells increased at day 5 and then gradually decreased). Urinary MDA levels at day 1 correlated significantly with Scr (rho = 0.721, P < 0.01) and tubular damage score (rho = 0.840, P < 0.01) at day 5.. Our findings demonstrated divergent changes of urinary oxidative stress markers in CDDP-induced ARF, and suggested that urinary MDA may be a useful marker for the prediction of the development of CDDP-induced ARF.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Animals; Biomarkers; Blotting, Western; Cisplatin; Deoxyguanosine; Disease Models, Animal; Disease Progression; Follow-Up Studies; Immunohistochemistry; Kidney Medulla; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Severity of Illness Index