Won-Min Hwang

Oxidative stress caused by activation of NADPH oxidase 4 promotes contrast-induced acute kidney injury

Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2’-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.

HELLP syndrome in a pregnant patient with Gitelman syndrome

Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypocalciuria, and hypomagnesemia. The clinical course of Gitelman syndrome in pregnant women remains unclear, but it is thought to be benign. We report here the first Korean case of atypical eclampsia in a 31-year-old who was diagnosed with Gitelman syndrome incidentally during an antenatal screening test. The patient did well during pregnancy despite significant hypokalemia. At 33 weeks’ gestation, the patient exhibited eclampsia, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and renal insufficiency without significant hypertension or proteinuria. We explain this unusual clinical course through a review of the relevant literature.

Exceptional mucocutaneous manifestations with amyloid nephropathy: a case report

BackgroundAmyloidosis is a very rare disease that is difficult to diagnose because of the unspecific early clinical manifestations of the disease. Accurate and early diagnosis is extremely important because the effect of treatment is dependent on the extent of disease progression. Sicca syndrome and nail dystrophy are very rare symptoms of amyloidosis. We report here a case of sicca syndrome and nail dystrophy with renal dysfunction in a 52-year-old Korean woman who was diagnosed as having systemic amyloidosis.Case presentationWe present the case of a 52-year-old Korean woman complaining of dry mouth and nail dystrophy for 4 months as an initial symptom. A slit lamp examination revealed superficial keratoconjunctival erosion in both eyes. A laboratory test showed anemia, azotemia, and proteinuria. Urine protein electrophoresis showed increased gamma globulin excretion. Serum free light chain of kappa and lambda were increased. Histopathological studies of biopsy specimens of minor salivary glands and kidney revealed deposits of amyloid fibrils. A bone marrow aspiration biopsy showed hypercellular marrow with 5% plasma cells. She was diagnosed as having primary systemic amyloidosis then started on chemotherapy.ConclusionSuch atypical mucocutaneous manifestations of amyloidosis can serve as important early diagnostic signs with less invasive biopsy confirmation in patients with systemic amyloidosis.

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

BackgroundnColistin (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.nnnObjectivesnWe investigated the role of Nox4 and benefit of Nox4 inhibition in colistin-induced acute kidney injury using in vivo and in vitro models.nnnMethodsnHuman 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.nnnResultsnNox4 expression in HK-2 cells significantly increased following colistin exposure. SB4315432 (transforming growth factor-β1 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.nnnConclusionsnCollectively, 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.