naphthoquinones and Acute-Kidney-Injury

Natural compounds were used in the treatment of acute kidney injury (AKI) caused by sepsis. This study investigated the function of shikonin from the roots of Arnebia purpurea in sepsis-induced AKI model. The target genes of shikonin were predicted by traditional Chinese medicine integrative database (TCMID). The markers of kidney injury, oxidative stress, and inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA). The pathological changes of kidney tubules were assessed by Hematoxylin and Eosin staining. Apoptosis of kidney tubular epithelial cells (KTECs) was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Protein expression was measured by western blot. Shikonin significantly improved kidney injury induced by cecal ligation and perforation (CLP). Besides, shikonin reduced KTECs apoptosis, malondialdehyde (MDA), reactive oxygen species (ROS), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels, while augmented SOD and IL-10 levels. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase4 (NOX4) was predicted a target gene of shikonin. The expression of NOX4 was significantly inhibited in shikonin-treated group and the levels of phosphatidylinositol 3,4,5-trisphosphate 3-phosphate and dual specificity protein phosphate (PTEN) and p-p65 were decreased, while level of p-Akt was elevated. In vitro experiments, shikonin inhibited cell apoptosis, inflammatory, and ROS in human HK-2 cells and rat TECs. Shikonin downregulated expression of NOX4, PTEN and p-p65, and upregulated p-AKT and Bcl-2 expression in HK2 cells treated with lipopolysaccharide (LPS). Moreover, overexpression of NOX4 enhanced the effect of LPS on the expression level of PTEN, p-p65, p-AKT, and Bcl-2, which was reversed by the addition of shikonin. Taken together, shikonin could improve sepsis-induced AKI in rats, and attenuate the LPS induced KTECs apoptosis, oxidative stress, and inflammatory reaction via modulating NOX4/PTEN/AKT pathway.

Topics: Acute Kidney Injury; Animals; Apoptosis; Epithelial Cells; Humans; Kidney; Lipopolysaccharides; NADPH Oxidase 4; Naphthoquinones; Oxidative Stress; Phosphates; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Rats; Reactive Oxygen Species; Sepsis

Pin1, as the peptidyl-prolyl isomerase, plays a vital role in cellular processes. However, whether it has a regulatory effect on renal ischemia and reperfusion (I/R) injury still remains unknown.. The hypoxia/reoxygenation (H/R) model in human kidney (HK-2) cells and the I/R model in rats were assessed to investigate the role of Pin1 on I/R-induced acute kidney injury. Male Sprague-Dawley rats were used to establish the I/R model for 15, 30, and 45 min ischemia and then 24 h reperfusion, with or without the Pin1 inhibitor, to demonstrate the role of Pin1 in acute kidney injury. HK-2 cells were cultured and experienced the H/R model to identify the molecular mechanisms involved.. In this study, we found that Pin1 and oxidative stress were obviously increased after renal I/R. Inhibition of Pin1 with juglone decreased renal structural and functional injuries, as well as oxidative stress. Besides, Pin1 inhibition with the inhibitor, juglone, or the small interfering RNA showed significant reduction on oxidative stress markers caused by the H/R process in vitro. Furthermore, the results indicated that the expression of p38 MAPK was increased during H/R in vitro and Pin1 inhibition could reduce the increased expression of p38 MAPK.. Our results illustrated that Pin1 aggravated renal I/R injury via elevating oxidative stress through activation of the p38 MAPK pathway. These findings indicated that Pin1 might become the potential treatment for renal I/R injury.

Topics: Acute Kidney Injury; Animals; Cell Line; Enzyme Inhibitors; Humans; Kidney; Male; MAP Kinase Signaling System; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Para-phenylenediamine is widely used as a chemical in hair dyes and in combination with henna. This dye is used to paint the body for decorative reasons, to speed the processing time of henna and to intensify the results. Para-phenylenediamine is widely used in the Middle East, North Africa and India. Several reports have been published of the fatal ingestion of hair dye containing para-phenylenediamine. Here, we describe the case of a 14-year-old girl who ingested the compound but whose prompt treatment prevented her death. Ingestion of para-phenylenediamine produces a typical triad of angioneurotic oedema, rhabdomyolysis and acute tubular necrosis. Awareness of signs of these associated conditions in our patient, together with a comprehensive history, facilitated appropriate treatment to be instituted. We document the steps we took to enable her complete physical recovery.

Topics: Acute Kidney Injury; Adolescent; Angioedema; Chlorpheniramine; Female; Fluid Therapy; Furosemide; Hair Dyes; Humans; Hydrocortisone; Naphthoquinones; Phenylenediamines; Respiration, Artificial; Rhabdomyolysis; Suicide, Attempted; Tracheostomy

Recent studies suggest a potential involvement of the Mre11-Rad50-Nbs1 (MRN) complex, a DNA double-strand breaks (DSBs) sensor, in the development of nephrotoxicity following cisplatin administration. β-Lapachone is a topoisomerase I inhibitor known to reduce cisplatin-induced nephrotoxicity. In this study, by assessing MRN complex expression, we explored whether β-lapachone was involved in DNA damage response in the context of cisplatin-induced nephrotoxicity.. Male Balb/c mice were randomly allocated to 4 groups: control, β-lapachone alone, cisplatin alone, and β-lapachone+cisplatin. β-Lapachone was administered with the diet (0.066%) for 2 weeks prior to cisplatin injection (18mg/kg). All mice were sacrificed 3 days after cisplatin treatment.. In the cisplatin-alone group, renal function was disrupted and MRN complex expression increased. As expected, β-lapachone co-treatment attenuated cisplatin-induced pathologic alterations. Notably, although β-lapachone markedly decreased cisplatin-induced renal cell apoptosis and DSBs formation, the β-lapachone+cisplatin group showed the highest MRN complex expression. Moreover, β-lapachone treatment increased the basal expression level of the MRN complex, which was accompanied by enhanced basal expression of SIRTuin1, which is known to regulate Nbs1 acetylation.. Although, it remains unclear how β-lapachone induces MRN complex expression, our findings suggest that β-lapachone might affect MRN complex expression and participate in DNA damage recovery in cisplatin-induced nephrotoxicity.

Topics: Acid Anhydride Hydrolases; Acute Kidney Injury; Animals; ATP-Binding Cassette Transporters; Cell Cycle Proteins; Cisplatin; DNA Damage; DNA Repair Enzymes; DNA-Binding Proteins; Gene Expression Regulation; Male; Mice; Mice, Inbred BALB C; MRE11 Homologue Protein; Naphthoquinones; Nuclear Proteins; Topoisomerase I Inhibitors

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD(+) is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD(+) levels by means of. quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1(-/-) mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD(+)/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1(-/-) mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD(+) levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Cisplatin; Mice, Inbred C57BL; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Sirtuin 1; Transcription Factor RelA

Ischemia/reperfusion (I/R) is the most common cause of acute renal injury. I/R-induced reactive oxygen species (ROS) are thought to be a major factor in the development of acute renal injury by promoting the initial tubular damage.. quinone oxidoreductase 1 (NQO1) is a well-known antioxidant protein that regulates ROS generation. The purpose of this study was to investigate whether NQO1 modulates the renal I/R injury (IRI) associated with NADPH oxidase (NOX)-derived ROS production in an animal model. We analyzed renal function, oxidative stress, and tubular apoptosis after IRI. NQO1(-/-) mice showed increased blood urea nitrogen and creatinine levels, tubular damage, oxidative stress, and apoptosis. In the kidneys of NQO1(-/-) mice, the cellular NADPH/NADP(+) ratio was significantly higher and NOX activity was markedly higher than in those of NQO1(+/+) mice. The activation of NQO1 by β-lapachone (βL) significantly improved renal dysfunction and reduced tubular cell damage, oxidative stress, and apoptosis by renal I/R. Moreover, the βL treatment significantly lowered the cellular NADPH/NADP(+) ratio and dramatically reduced NOX activity in the kidneys after IRI. From these results, it was concluded that NQO1 has a protective role against renal injury induced by I/R and that this effect appears to be mediated by decreased NOX activity via cellular NADPH/NADP(+) modulation. These results provide convincing evidence that NQO1 activation might be beneficial for ameliorating renal injury induced by I/R.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Enzyme Activators; Gene Expression; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); NADP; NADPH Oxidases; Naphthoquinones; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury

Topics: Acute Kidney Injury; Administration, Cutaneous; Coloring Agents; Female; Hair Dyes; Humans; Middle Aged; Naphthoquinones; Phenylenediamines; Renal Dialysis

NADPH oxidase (NOX) is a predominant source of reactive oxygen species (ROS), and the activity of NOX, which uses NADPH as a common rate-limiting substrate, is upregulated by prolonged dietary salt intake. β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), decreases the cellular NAD(P)H/NAD(P)(+) ratio via activation of NQO1. In this study, we evaluated whether NQO1 activation by βL modulates salt-induced renal injury associated with NOX-derived ROS regulation in an animal model. Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet were used to investigate the renoprotective effect of NQO1 activation. βL treatment significantly lowered the cellular NAD(P)H:NAD(P)(+) ratio and dramatically reduced NOX activity in the kidneys of HS diet-fed DS rats. In accordance with this, total ROS production and expression of oxidative adducts also decreased in the βL-treated group. Furthermore, HS diet-induced proteinuria and glomerular damage were markedly suppressed, and inflammation, fibrosis, and apoptotic cell death were significantly diminished by βL treatment. This study is the first to demonstrate that activation of NQO1 has a renoprotective effect that is mediated by NOX activity via modulation of the cellular NAD(P)H:NAD(P)(+) ratio. These results provide strong evidence that NQO1 might be a new therapeutic target for the prevention of salt-induced renal injury.

Topics: Acute Kidney Injury; Animals; Apoptosis; Enzyme Activation; Enzyme Activators; Fibrosis; Inflammation; Kidney Glomerulus; Male; NAD(P)H Dehydrogenase (Quinone); NADP; NADPH Oxidases; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium Chloride

Poisoning by a mixture of henna dye and para-phenylenediamine dyes led to the hospitalization of 31 Sudanese children between 1984 and 1989. There was a characteristic clinical presentation. All children presented with an acute and severe angioneurotic oedema and 15 of the cases required emergency tracheostomy for respiratory obstruction. Acute renal failure occurred in five children who recovered after peritoneal dialysis. Mortality was high, all 13 deaths occurring within 24 hours of presentation. Hypotensive shock gave a poor prognosis. It is possible that similar cases may be occurring unrecognized where henna is traditionally used. A programme of public education and restriction of para-phenylenediamine is urgently required in The Sudan and other affected nations. Ingestion was accidental in 12 children, deliberate in 10 and homicidal in three cases. Cutaneous absorption was likely in the remaining six.

Topics: Acute Kidney Injury; Adolescent; Angioedema; Child; Child, Preschool; Female; Hair Dyes; Humans; Lung Diseases, Obstructive; Male; Naphthoquinones; Phenylenediamines; Sudan

We have previously demonstrated that administration of various benzoquinol-glutathione (GSH) conjugates to rats causes renal proximal tubular necrosis and the initial lesion appears to lie within that portion of the S3 segment within the outer stripe of the outer medulla (OSOM). The toxicity may be a consequence of oxidation of the quinol conjugate to the quinone followed by covalent binding to tissue macromolecules. We have therefore synthesized the GSH and N-acetylcysteine conjugates of 2-methyl-1,4-naphthoquinone (menadione) and 1,4-naphthoquinone. The resulting conjugates have certain similarities to the benzoquinol-GSH conjugates, but the main difference is that reaction with the thiol yields a conjugate which remains in the quinone form. 2-Methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone caused a dose-dependent (50-200 mumol/kg) necrosis of the proximal tubular epithelium. The lesion involved the terminal portion of the S2 segment and the S3 segment within the medullary ray. At the lower doses, that portion of the S3 segment in the outer stripe of the outer medulla displayed no evidence of necrosis. In contrast, 2-methyl-3-(glutathion-S-yl)-1,4-naphthoquinone (200 mumol/kg) caused no apparent histological alterations to the kidney. 2-(Glutathion-S-yl)-1,4-naphthoquinone and 2,3-(diglutathion-S-yl)-1,4-naphthoquinone (200 mumol/kg) were relatively weak proximal tubular toxicants and the lesion involved the S3 segment at the junction of the medullary ray and the OSOM. A possible reason(s) for the striking difference in the toxicity of the N-acetylcysteine conjugate of menadione, as opposed to the lack of toxicity of the GSH conjugate of menadione, is discussed. The basis for the localization of the lesion caused by 2-methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone requires further study.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Blood Urea Nitrogen; Glutathione; Kidney Cortex; Kidney Medulla; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Magnetic Resonance Spectroscopy; Male; Naphthoquinones; Rats; Rats, Inbred Strains; Vitamin K