A Large Pleomorphic Adenoma in Nasal Cavity Misdiagnosed as Inverted Papilloma.

Pleomorphic adenoma (PA) is a benign tumor characterized by slow-growing mixed tumors in the craniofacial area. It is relatively common in salivary glands; however, PA of the nasal cavity, which arises in the minor salivary glands, is rare. We present the case of a large PA in the nasal cavity of an adult immunocompetent woman with nasal obstruction and intermittent epistaxis. Based on preoperative radiologic examinations, she was misdiagnosed with an inverted papilloma. Endoscopic resection was performed under general anesthesia. Pathologically, the patient was confirmed to have PA, which has great cellularity and few stromal components. No complications or recurrences during the 1-year follow-up period were observed.

Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease.

BACKGROUND: Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid-polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD. RESULTS: Gb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old male B6;129-Glatm1Kul/J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved. CONCLUSIONS: PEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease.

Effects and Mechanism of Particulate Matter on Tendon Healing Based on Integrated Analysis of DNA Methylation and RNA Sequencing Data in a Rat Model.

Exposure to particulate matter (PM) has been linked with the severity of various diseases. To date, there is no study on the relationship between PM exposure and tendon healing. Open Achilles tenotomy of 20 rats was performed. The animals were divided into two groups according to exposure to PM: a PM group and a non-PM group. After 6 weeks of PM exposure, the harvest and investigations of lungs, blood samples, and Achilles tendons were performed. Compared to the non-PM group, the white blood cell count and tumor necrosis factor-alpha expression in the PM group were significantly higher. The Achilles tendons in PM group showed significantly increased inflammatory outcomes. A TEM analysis showed reduced collagen fibrils in the PM group. A biomechanical analysis demonstrated that the load to failure value was lower in the PM group. An upregulation of the gene encoding cyclic AMP response element-binding protein (CREB) was detected in the PM group by an integrated analysis of DNA methylation and RNA sequencing data, as confirmed via a Western blot analysis showing significantly elevated levels of phosphorylated CREB. In summary, PM exposure caused a deleterious effect on tendon healing. The molecular data indicate that the action mechanism of PM may be associated with upregulated CREB signaling.

TGF-ß-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury.

Background: Colistin (polymyxin E) is an important constituent of the polymyxin class of cationic polypeptide antibiotics. Intrarenal oxidative stress can contribute to colistin-induced nephrotoxicity. Nicotinamide adenine dinucleotide 3-phosphate oxidases (Noxs) are important sources of reactive oxygen species. Among the various types of Noxs, Nox4 is predominantly expressed in the kidney. Objectives: We investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models. Methods: Human proximal tubular epithelial (HK-2) cells were treated with colistin with or without NOX4 knockdown, or GKT137831 (most specific Nox1/4 inhibitor). Effects of Nox4 inhibition on colistin-induced acute kidney injury model in Sprague-Dawley rats were examined. Results: Nox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells. Knockdown of NOX4 transcription reduced reactive oxygen species production, lowered the levels of pro-inflammatory markers (notably mitogen-activated protein kinases) implicated in colistin-induced nephrotoxicity and attenuated apoptosis by altering Bax and caspase 3/7 activity. Pretreatment with GKT137831 replicated these effects mediated by downregulation of mitogen-activated protein kinase activities. In a rat colistin-induced acute kidney injury model, administration of GKT137831 resulted in attenuated colistin-induced acute kidney injury as indicated by attenuated impairment of glomerulus function, preserved renal structures, reduced expression of 8-hydroxyguanosine and fewer apoptotic cells. Conclusions: Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.

Epithelioid trophoblastic tumor presenting as an ovarian mass in a postmenopausal woman.

Epithelioid trophoblastic tumor (ETT) is a rare neoplasm derived from chorionic-type intermediate trophoblastic cells. Most cases of ETT are intrauterine and present during reproductive age. We report a case of ovarian ETT developing 47 yr after the patient's last pregnancy. A 75-yr-old woman transferred to our hospital because of multiple pulmonary masses which was diagnosed as sqaumous cell carcinoma in another hospital. PET-CT revealed a huge solid mass in the pelvic cavity, suspicious for ovarian malignancy. Serum ß-hCG was 57,971 mIU/mL. Hysterectomy and bilateral salpingo-oophorectomy were performed. Gross examination showed an enlarged right ovary, measuring 17×14×7 cm. The cut surface was yellow-tan and solid with extensive areas of necrosis. The uterus was unremarkable. The histologic finding was the same as the previous lung biopsy. The tumor consisted of monomorphic cells with abundant eosinophilic cytoplasm, forming solid sheets and nests. There was geographic tumor cell necrosis with hyaline materials. Immunohistochemically, cytokeratin 7 and p63 showed diffuse reactivity in the tumor cells. There was focal staining for ß-hCG. Ki-67 proliferative index was about 80%. This case indicates that ETT can rarely occur in postmenopausal women and to the best of our knowledge, our patient is the oldest reported case of ETT to date.

A Rare Case of Stroke in a 76-Year-Old Woman: Left Atrial Papillary Fibroelastoma as the Culprit.

BACKGROUND Papillary fibroelastoma is the most common type of benign primary cardiac tumor and is usually asymptomatic. However, tumor fragments or surface thrombus can embolize and cause transient ischemic attacks, strokes, or myocardial infarction. This report describes a 76-year-old woman who presented with dysarthria and right-sided weakness due to a stroke associated with a left atrial papillary fibroelastoma. CASE REPORT A 76-year-old woman visited the Emergency Department because she had right-sided weakness and dysarthria from 12 h ago. Brain magnetic resonance image was done at the Emergency Department, showing multiple small embolic, acute infarction in left basal ganglia and fronto-temporo-parietal lobes. Transthoracic and transesophageal echocardiogram showed a hypermobile echogenic mass (0.8×1.5 cm) with villous surface on the orifice of left atrial appendage. Twenty-four-hour Holter monitoring was performed to evaluate the cause of cerebral infarction, and there was no paroxysmal atrial fibrillation. Thoracic computed tomography angiography also showed a sea anemone-shaped mass around the left atrial appendage. Cardiac tumor excision was done via a lower partial sternotomy. Histopathologic analysis showed multiple delicate fronds, and the avascular fibroelastic cores were lined by a single layer of CD31-positive endothelial cells. Histopathologic findings were consistent with papillary fibroelastoma. The patient was discharged without any other complications on day 30 of hospitalization. CONCLUSIONS This case highlights the importance of cardiac imaging in patients with acute stroke, including transthoracic and transesophageal echocardiography, which can show the typical imaging features of papillary fibroelastoma and other intracardiac sources of embolus.

Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3.

Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1ß, Wilms' tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient's survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%, respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival (P<0.05). High Galectin-3 (≥80%) expression was seen in 59.7% of CCCs, and associated with FIGO stages III and IV, and high Ki-67 labeling index. High Ki-67 labeling index (≥50%) and p53 expression (≥50%) were seen in 27.1% and 18.6% of CCCs, respectively, but there was no clinicopathologic and prognostic significance. On the basis of the fact that the expression of Emi1 in CCC was correlated with a high histologic grade and worse overall survival, target therapy using inhibitors of Emi1 may be tried in the management of CCC patients with Emi1 expression.

A case of microscopic polyangiitis associated with aortic valve insufficiency.

Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by inflammation of small-sized vessels. Although there have been some reports of ANCA-associated vasculitis presenting as aortitis syndrome, MPA rarely involves large-sized vessels such as the aorta. We report an unusual case of MPA combined with severe acute aortic valve insufficiency in a 56-year-old man. He initially presented with prolonged fever, skin rash, and rapidly progressive glomerulonephritis. P-ANCA and anti-myeloperoxidase (MPO) antibodies were positive, but the c-ANCA and anti-proteinase-3 antibodies were negative. Skin biopsy of the lower leg showed necrotizing arteritis. Kidney biopsy was also performed, which revealed diffuse necrotizing and crescentic glomerulonephritis (GN) consistent with pauci-immune ANCA-associated GN. Serial echocardiographic evaluations revealed aortic valve changes and worsening acute aortic valve insufficiency over a two-month period. Despite intensive treatment, our patient developed sudden cardiac arrest and died. Our patient demonstrated typical clinical features and histopathologic findings for systemic vasculitis and had a positive anti-MPO antibody, all of which were consistent with the diagnosis of MPA. Thus, MPA may have been the cause of acute aortic valve insufficiency in this case.

Bilateral renal cortical necrosis following binge drinking.

Renal cortical necrosis (RCN) is a rare cause of acute kidney injury secondary to ischemic necrosis of the renal cortex. Acute tubular necrosis after binge drinking is usually attributed to volume depletion, idiosyncratic reaction to alcohol, rhabdomyolysis or a combination with non-steroidal anti-inflammatory drugs. Binge drinking itself as a cause of RCN has not yet been reported. We report a case of a 25-year-old Asian male who developed bilateral RCN following binge drinking.

A case of elderly-onset Crescentic Henoch-Schönlein purpura nephritis with hypocomplementemia and positive MPO-ANCA.

Henoch-Schönlein purpura (HSP) is common in childhood and often self-limiting. There have been limited studies on elderly-onset HSP nephritis (HSPN). A 76-yr-old man was transferred to our hospital with a 1-month history of oliguria, abdominal pain, edema and palpable purpura in the legs. Three months ago, he was admitted to another hospital with jaundice, and consequently diagnosed with early common bile duct cancer. The patient underwent a Whipple's operation. Antibiotics were administrated because of leakage in the suture from the surgery. However, he showed progressive renal failure with edema and purpura in the legs. Laboratory investigations showed serum creatinine 6.4 mg/dL, 24-hr urine protein 8,141 mg/day, myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) 1:40 and C(3) below 64.89 mg/dL. Renal biopsy showed crescentic glomerulonephritis, as well as mesangial and extracapillary Ig A deposition. We started steroid therapy and hemodialysis, but he progressed to end-stage renal failure and he has been under maintenance hemodialysis. We describe elderly onset HSPN with MPO-ANCA can be crescentic glomerulonephritis rapidly progressed to end stage renal failure.

Acute kidney injury due to intravenous detergent poisoning: A case report.

BACKGROUND: Detergent poisoning mostly occurs through oral ingestion (> 85%), ocular exposure (< 15%), or dermal exposure (< 8%). Reports of detergent poisoning through an intravenous injection are extremely rare. In addition, there are very few cases of renal toxicity directly caused by detergents. Here, we report a unique case of acute kidney injury caused by detergent poisoning through an accidental intravenous injection. CASE SUMMARY: A 61-year-old man was intravenously injected with 20 mL of detergent by another patient in the same room of a local hospital. The surfactant and calcium carbonate accounted for the largest proportion of the detergent. The patient complained of vascular pain, chest discomfort, and nausea, and was transferred to our institution. After hospitalization, the patient's serum creatinine level increased to 5.42 mg/dL, and his daily urine output decreased to approximately 300 mL. Renal biopsy findings noted that the glomeruli were relatively intact; however, diffuse acute tubular injury was observed. Generalized edema was also noted, and the patient underwent a total of four hemodiafiltration sessions. Afterward, the patient's urine output gradually increased whereas the serum creatinine level decreased. The patient was discharged in a stable status without any sequelae. CONCLUSION: Detergents appear to directly cause renal tubular injury by systemic absorption. In treating a patient with detergent poisoning, physicians should be aware that the renal function may also deteriorate. In addition, timely renal replacement therapy may help improve the patient's prognosis.

Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis.

BACKGROUND: Cisplatin chemotherapy often causes acute kidney injury in cancer patients. The causative mechanisms of cisplatin-induced acute kidney injury include renal inflammation, activation of p53 tumour suppressor protein and tubular apoptosis. Luteolin, a flavone found in medicinal herbs and plants, has been reported to exhibit anti-inflammatory, antioxidant and anticarcinogenic activities. The purpose of this study was to investigate the anti-apoptotic effect of luteolin on cisplatin-induced acute kidney injury and the molecular mechanism. METHODS: C57BL/6 mice were treated with cisplatin (20 mg/kg) with or without treatment with luteolin (50 mg/kg for 3 days). Renal function, histological changes, degree of oxidative stress and tubular apoptosis were examined. The effects of luteolin on cisplatin-induced expression of renal p53, PUMA-α and Bcl-2 family proteins were evaluated. RESULTS: Treatment of mice with cisplatin resulted in renal damage, showing an increase in blood urea nitrogen and creatinine levels, tubular damage, oxidative stress and apoptosis. Treatment of cisplatin-treated mice with luteolin significantly improved renal dysfunction, reducing tubular cell damage, oxidative stress and apoptosis. Examination of molecules involving apoptosis of the kidney revealed that treatment of cisplatin increased the levels of p53 and its phosphorylation, PUMA-α, Bax and caspase-3 activity that were significantly decreased by treatment with luteolin. CONCLUSION: These results indicate that cisplatin induces acute kidney injury by regulation of p53-dependent renal tubular apoptosis and that luteolin ameliorates the cisplatin-mediated nephrotoxicity through down-regulation of p53-dependent apoptotic pathway in the kidney.

Intravascular myopericytoma: an interesting case of a long-standing large, painful subcutaneous tumor.

Myopericytoma is a benign neoplasm consisting of cells that appear to have a distinct differentiation towards presumed perivascular myoid cells. Amongst myopericytoma, an intravascular variant appears to have been reported only rarely. A 67-year-old man presented with a 15-year history of a painful, slow growing 3 × 3.5 cm sized mass in the subcutis of his right lateral thigh. Histopathological studies showed a subcutaneous mass entirely within the lumen of a vein. The tumor was composed of spindle-shaped myoid-appearing cells in a concentric arrangement, intimately associated with thin-walled vascular channels. Tumor cells were diffusely positive for smooth muscle actin, focally positive for CD34, and negative for desmin and CD31. From these findings, we diagnosed this lesion as intravascular myopericytoma. Unlike previous reports, our case showed a relatively large painful subcutaneous mass, although this tumor has an intravascular nature.

Prognostic associations of clinical and histopathological features in renal amyloidosis.

AIM: This retrospective study was conducted to assess the relationship between renal functional parameters and histolopathological findings in patients with renal amyloidosis. METHODS: A total of 40 patients with biopsy-proven renal amyloidosis, which was diagnosed at the Department of Pathology, Hanyang University Hospital, between 1986 and 2010, were investigated. Renal biopsy specimens were evaluated in various histochemical and immunohistochemical stains using light, immunofluorescence and electron microscopes, and renal function was determined by estimated glomerular filtration rate (eGFR) (ml/min/1.73 m(2)) using the method proposed by the Modification of Diet in Renal Disease study. Glomerular amyloid deposits were classified into four groups: none, mild, segmental and diffuse types. The vascular, tubular and interstitial deposits were subdivided into the negative and positive groups. RESULTS: In simple regression analysis, 24-hour protein excretion, serum blood urea nitrogen and eGFR were found to significantly correlate with the increased extent of glomerular amyloid deposit. In multiple regression analysis, a decrease in eGFR was significantly associated with an increase in glomerular amyloid deposits (p=0.024), but there was no significant correlation with an increase in 24-hour protein excretion and blood urea nitrogen (p=0.119 and 0.184, respectively). CONCLUSION: The results of this study demonstrate that the increased extent of glomerular amyloid deposits may be associated with the decline of GFR in patients with renal amyloidosis.

Collapsing focal segmental glomerulosclerosis in a patient with oral cavity cancer: A case report.

RATIONALE: Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases, leading to end-stage renal disease. Among the 5 variants of FSGS, the collapsing variant is rare and has the worst prognosis. Solid and hematologic malignancies are associated with glomerular diseases, such as membranous nephropathy, minimal change disease, and FSGS. However, squamous cell carcinoma of the oral cavity is rarely associated with nephrotic syndrome, especially FSGS. PATIENT CONCERNS: A 55-year-old woman diagnosed with oral cavity cancer presented with generalized edema with heavy proteinuria and renal dysfunction after neoadjuvant chemotherapy and wide surgical excision. DIAGNOSIS: Renal biopsy shows segmental or global collapse of glomerular capillaries with marked hyperplasia and swelling of overlying epithelial cells, suggesting a collapsing variant of FSGS. INTERVENTIONS: After the renal biopsy, we prescribed oral prednisolone at a dose of 1 mg/kg/day. Despite immunosuppressive treatment, renal function deteriorated, and hemodialysis was started. OUTCOMES: After 23 sessions of hemodialysis and high-dose oral glucocorticoid treatment, renal function gradually improved, and oral glucocorticoid therapy was discontinued after 8 months. Currently, this patient is in a cancer-free state and has normal renal function without proteinuria. LESSONS: Unusual collapsing FSGS might be associated with neoadjuvant chemotherapy and wide surgical excision in patients with oral cavity cancer. Proper diagnostic workup, such as renal biopsy and high-dose glucocorticoid therapy, might have helped recover from nephrotic syndrome and acute renal injury in cancer patients.

Locally delivered growth factor enhances the angiogenic efficacy of adipose-derived stromal cells transplanted to ischemic limbs.

Ischemia is a potentially fatal medical event that is associated with as many as 30% of all deaths. Stem cell therapy offers significant therapeutic promise, but poor survival following transplantation to ischemic tissue limits its efficacy. Here we demonstrate that nanosphere-mediated growth factor delivery can enhance the survival of transplanted human adipose-derived stromal cells (hADSCs) and secretion of human angiogenic growth factors per cell, and substantially improve therapeutic efficacy of hADSCs. In vitro, in hypoxic (1% oxygen) and serum-deprived conditions that simulate in vivo ischemia, fibroblast growth factor-2 (FGF2) significantly reduced hADSC apoptosis and enhanced angiogenic growth factor secretion. In vivo, hADSCs delivered intramuscularly into ischemic hind limbs in combination with FGF2 resulted in significant improvements in limb survival and blood perfusion, as well as survival of the transplanted hADSCs and secretion of human angiogenic growth factors (i.e., vascular endothelial growth factor, hepatocyte growth factor, and FGF2). Interestingly, the majority of transplanted hADSCs were localized adjacent to the microvessels rather than being incorporated into them, suggesting that their major contribution to angiogenesis might be to increase paracrine secretion of angiogenic growth factors. This study demonstrates the potential of hADSCs in combination with growth factors for use in the treatment of ischemia.

Cyclic mechanical strain promotes transforming-growth-factor-beta1-mediated cardiomyogenic marker expression in bone-marrow-derived mesenchymal stem cells in vitro.

Cardiomyocytes in the heart reside in mechanically dynamic environments, such as those subject to cyclic mechanical strain. TGF-beta1 (transforming growth factor-beta1) stimulates cardiomyogenic marker expression of BMMSCs (bone-marrow-derived mesenchymal stem cells). In the present study, we tested the hypothesis that cyclic mechanical strain promotes TGF-beta1-mediated cardiomyogenic marker expression in BMMSCs in vitro. The mRNA expression of cardiac-specific genes was more up-regulated in BMMSCs cultured with a TGF-beta1 supplement and subjected to cyclic strain for 1 week than in BMMSCs cultured statically with a TGF-beta1 supplement. Immunocytochemical analyses and flow cytometric analysis showed that the proportions of cardiac troponin-I-positive cells and cardiac MHC (myosin heavy chain)-positive cells and the proportions of cells expressing tropomyosin respectively were increased to a greater extent by TGF-beta1with cyclic strain than by TGF-beta1 alone. These results showed that cyclic strain promotes TGF-beta1mediated cardiomyogenic marker expression in BMMSCs in vitro.

Plant-derived angiogenin fusion protein's cytoprotective effect on trabecular meshwork damage induced by Benzalkonium chloride in mice.

BACKGROUND: Benzalkonium chloride (BAK), commonly used in glaucoma treatment, is an eye drop preservative with dose-dependent toxicity. Previous studies have observed the multi-functional benefits of angiogenin (ANG) against glaucoma. In our study, we evaluated ANG's cytoprotective effect on the trabecular meshwork (TM) damage induced by BAK. Additionally, we developed a plant-derived ANG fusion protein and evaluated its effect on TM structure and function. METHODS: We synthesized plant-derived ANG (ANG-FcK) by fuzing immunoglobulin G's Fc region and KDEL to conventional recombinant human ANG (Rh-ANG) purified from transgenic tobacco plants. We established a mouse model using BAK to look for degenerative changes in the TM, and to evaluate the protective effects of ANG-FcK and Rh-ANG. Intraocular pressure (IOP) was measured for 4 weeks and ultrastructural changes, deposition of fluorescent microbeads, type I and IV collagen, fibronectin, laminin and α-SMA expression were analyzed after the mice were euthanized. RESULTS: TM structural and functional degeneration were induced by 0.1% BAK instillation in mice. ANG co-treatment preserved TM outflow function, which we measured using IOP and a microbead tracer. ANG prevented phenotypic and ultrastructure changes, and that protective effect might be related to the anti-fibrosis mechanism. We observed a similar cytoprotective effect in the BAK-induced degenerative TM mouse model, suggesting that plant-derived ANG-FcK could be a promising glaucoma treatment.

Ceria-Zirconia Antioxidant Nanoparticles Attenuate Hypoxia-Induced Acute Kidney Injury by Restoring Autophagy Flux and Alleviating Mitochondrial Damage.

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

NADPH oxidase 4 mediates TGF-ß1/Smad signaling pathway induced acute kidney injury in hypoxia.

Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-ß1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-ß1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.