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Featured researches published by Gang Jee Ko.


Nephrology Dialysis Transplantation | 2008

Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats

Gang Jee Ko; Young Sun Kang; Sang Youb Han; Mi Hwa Lee; Hye Kyoung Song; Kum Hyun Han; Hyoung Kyu Kim; Jee Young Han; Dae Ryong Cha

BACKGROUND Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a role in insulin sensitivity, lipid metabolism and inflammation. However, the effects of PPARgamma agonist on renal inflammation have not been fully examined in type 2 diabetic nephropathy. METHODS In the present study, we investigated the effect and molecular mechanism of the PPARgamma agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-kappaB, MCP-1 and pro-fibrotic cytokines were determined by RT-PCR, western blot, immunohistochemical staining and EMSA. In addition, to evaluate the direct anti-inflammatory effect of PPARgamma agonist, we performed an in vitro study using mesangial cells. RESULTS Treatment of OLETF rats with pioglitazone improved insulin sensitivity and kidney/body weight, but had a little effect on blood pressure. Pioglitazone treatment markedly reduced urinary albumin and MCP-1 excretion, and ameliorated glomerulosclerosis. In cDNA microarray analysis using renal cortical tissues, several inflammatory and profibrotic genes were significantly down-regulated by pioglitazone including NF-kappaB, CCL2, TGFbeta1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-kappaB activation in association with a decrease in type IV collagen, PAI-1, and TGFbeta1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPARgamma transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-kappaB activation. CONCLUSIONS These data suggest that pioglitazone not only improves insulin resistance, glycaemic control and lipid profile, but also ameliorates renal injury through an anti-inflammatory mechanism in type 2 diabetic rats.


Kidney International | 2010

CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice

Young Sun Kang; Mi Hwa Lee; Hye Kyoung Song; Gang Jee Ko; Oh Sung Kwon; Tae Kyung Lim; Sung Hwan Kim; Sang Youb Han; Kum Hyun Han; Ji Eun Lee; Jee Young Han; Hyoung Kyu Kim; Dae Ryong Cha

Chemokine ligand 2 (CCL2) binds to its receptor C-C chemokine receptor 2 (CCR2), initiating tissue inflammation, and recent studies have suggested a beneficial effect of a blockade of this pathway in diabetic nephropathy. To investigate the mechanism of protection, we studied the effect of RS504393, a CCR2 antagonist, on insulin resistance and diabetic nephropathy in db/db mice. Administering this antagonist improved insulin resistance as confirmed by various biomarkers, including homeostasis model assessment index levels, plasma insulin levels, and lipid abnormalities. Mice treated with the antagonist had a significant decrease in epididymal fat mass as well as phenotypic changes of adipocytes into small differentiated forms with decreased CCL2 expression and lipid hydroperoxide levels. In addition, treatment with the CCR2 antagonist markedly decreased urinary albumin excretion, mesangial expansion, and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, the CCR2 antagonist improved lipid metabolism, lipid hydroperoxide, cholesterol, and triglyceride contents of the kidney, and decreased urinary 8-isoprostane levels. Hence, our findings suggest that CCR2 antagonists can improve insulin resistance by modulation of the adipose tissue and restore renal function through both metabolic and anti-fibrotic effects in type 2 diabetic mice.


American Journal of Physiology-renal Physiology | 2008

Visfatin: a new player in mesangial cell physiology and diabetic nephropathy

Hye Kyoung Song; Mi Hwa Lee; Bo Kyung Kim; Yun Gyu Park; Gang Jee Ko; Young Sun Kang; Jee Young Han; Sang Youb Han; Kum Hyun Han; Hyoung Kyu Kim; Dae Ryong Cha

Visfatin is an adipocytokine that improves insulin resistance and has an antidiabetic effect. However, the role of visfatin in the kidney has not yet been reported. In this experiment, the synthesis and physiological action of visfatin in cultured mesangial cells (MCs) were studied to investigate the role of visfatin in diabetic nephropathy. Visfatin was found synthesized in MCs as well as adipocytes. Visfatin synthesis was markedly increased, not by angiotensin II, but by high glucose stimuli. In addition, visfatin treatment induced a rapid uptake of glucose, peaking at 20 min after visfatin treatment in a dose-dependent manner. A small inhibiting RNA against insulin receptor significantly blocked visfatin-mediated glucose uptake. Visfatin stimuli also enhanced intracellular NAD levels, and treatment with FK866, which is a specific inhibitor of nicotinamide phosphoribosyltransferase (Nampt), significantly inhibited visfatin-induced NAD synthesis and glucose uptake. Visfatin treatment increased glucose transporter-1 (GLUT-1) protein expression in isolated cellular membranes, and pretreatment with cytochalasin B completely inhibited visfatin-induced glucose uptake. Moreover, immunofluorescent microscopy showed the migration of cytosolic GLUT-1 into cellular membranes after visfatin treatment. In accordance with these results, the activation of protein kinase B was detected after visfatin treatment. Furthermore, visfatin treatment dramatically increased the synthesis of profibrotic molecules including transforming growth factor-beta1, plasminogen activator inhibitor-1, and type I collagen, and pretreatment with cytochalasin B completely inhibited visfatin-induced upregulation of profibrotic molecules. These results suggest that visfatin is produced in MCs, which are a novel target for visfatin, and play an important role in the pathogenesis of diabetic nephropathy.


Journal of The American Society of Nephrology | 2006

Heat Preconditioning Attenuates Renal Injury in Ischemic ARF in Rats: Role of Heat-Shock Protein 70 on NF-κB–Mediated Inflammation and on Tubular Cell Injury

Sang Kyung Jo; Gang Jee Ko; Chang Su Boo; Won Yong Cho; Hyoung Kyu Kim

Although heat preconditioning has been known to be protective in various types of injury, the precise molecular mechanism for this is unclear. Recent observations that indicate that previous heat shock has an anti-inflammatory, antiapoptotic effect led to this investigation of the in vivo effect of heat preconditioning on NF-kappaB activation and inflammation and also on tubular cell injury in ischemic acute renal failure (ARF). Heat preconditioning provided marked functional protection and also reduced histologic evidence of tubular necrosis. Ischemia/reperfusion-induced NF-kappaB activation was suppressed by heat preconditioning with a subsequent decrease in monocyte chemoattractant protein-1 expression and inflammatory cell infiltration. Heat preconditioning also suppressed the accumulation of phosphorylated inhibitory kappaBalpha (IkappaBalpha) with a resultant depletion of cytoplasmic IkappaBalpha, indicating that heat preconditioning blocked the activation of the IkappaB kinase complex. Tubular cell apoptosis, determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, also was decreased by heat preconditioning, and this was accompanied by decreased caspase 3 activation. Among several heat-shock proteins (HSP), HSP-70 was induced primarily by heat preconditioning. Inhibition of HSP-70 by quercetin almost completely reversed the functional protection that was provided by heat preconditioning. These data provide evidence that HSP-70 affords protection via inhibition of NF-kappaB-mediated inflammation and also inhibition of the cell death pathway in ischemic ARF. Further elucidation of the cytoprotective mechanism of stress proteins could facilitate new target or drug development in the treatment of ARF.


Nephrology Dialysis Transplantation | 2008

Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats

Young Sun Kang; Gang Jee Ko; Mi Hwa Lee; Hye Kyoung Song; Sang Youb Han; Kum Hyun Han; Hyoung Kyu Kim; Jee Young Han; Dae Ryong Cha

BACKGROUND Recent data suggest that aldosterone antagonists have beneficial effects on diabetic nephropathy. In this study, we investigated the dose-dependent effect of eplerenone and a combined treatment with eplerenone and enalapril compared with each drug alone on renal function in type II diabetic rats. To further explore the molecular mechanism of action of combination therapy, we also performed in vitro study. METHODS The animals were divided into six groups as follows: normal control Long-Evans Tokushima Otsuka (LETO) rats, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, OLETF rats treated with low dose of eplerenone (50 mg/kg/day), OLETF rats treated with high dose of eplerenone (200 mg/kg/day), OLETF rats treated with enalapril (10 mg/kg/day) and OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and enalapril 10 mg/kg/day) for 6 months. RESULTS Treatment of OLETF rats had no significant effect on body weight, kidney weight and blood glucose levels. However, urinary albumin excretion, glomerular filtration rate and glomerulosclerosis were significantly improved in the enalapril group and improvement was observed in a dose-dependent manner in the eplerenone groups; the most dramatic decreases were observed in the combination group. In accordance with these findings, renal expressions of TGF-beta1, type IV collagen and PAI-1 were also markedly decreased in the treatment groups, with the combined treatment providing the most significant level of improvement. In cultured mesangial cells, combined treatment resulted in an additive decrease in TGF-beta1, PAI-1 and collagen gene expressions and protein production induced by high glucose and aldosterone stimulation. CONCLUSIONS Aldosterone receptor antagonism provided additional benefits beyond blockade of the renin-angiotensin system in type II diabetic nephropathy.


Nephrology Dialysis Transplantation | 2011

Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice

Young Sun Kang; Mi Hwa Lee; Hye Kyoung Song; Young Youl Hyun; Jin Joo Cha; Gang Jee Ko; Sung Hwan Kim; Ji Eun Lee; Jee Young Han; Dae Ryong Cha

BACKGROUND Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs). RESULTS Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism. CONCLUSIONS Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.


Diabetes Research and Clinical Practice | 2010

Plasma concentration of visfatin is a new surrogate marker of systemic inflammation in type 2 diabetic patients

Young Sun Kang; Hye Kyoung Song; Mi Hwa Lee; Gang Jee Ko; Dae Ryong Cha

It is not clear whether plasma visfatin level is related with systemic inflammation or diabetic nephropathy in diabetic patients. In this study, we investigated the relationship between plasma visfatin levels and systemic inflammation or diabetic nephropathy in type 2 diabetic patients. In addition, we examined the physiological action of visfatin in cultured adipocytes in diabetic condition. Plasma visfatin concentrations were significantly higher in the diabetic groups than in the controls. Plasma visfatin levels were positively correlated with systolic blood pressure, body weight, fasting blood glucose, plasma levels of MCP-1, urinary albumin excretion (UAE), and carotid intima-media thickness (IMT), and were inversely correlated with plasma adiponectin, and creatinine clearance. However, plasma visfatin concentrations did not show a significant relationship with HbA1C, BMI or HOMA-IR. Regression analysis showed that plasma levels of MCP-1 and UAE were only independent determinants of plasma visfatin concentration. In cultured adipocytes, high glucose and angiotensin II stimuli markedly increased visfatin synthesis. Exogenous visfatin treatment significantly decreased differentiation of adipocytes and increased NF-kappaB transcriptional activity and pro-inflammatory molecules in adipocytes. These findings suggest that visfatin synthesis is activated from adipose tissue in a diabetic environment, induces NF-kappaB activation and leads to activation of pro-inflammatory cytokines and systemic inflammation.


Kidney International | 2010

Visfatin is upregulated in type-2 diabetic rats and targets renal cells

Young Sun Kang; Hye Kyoung Song; Mi Hwa Lee; Gang Jee Ko; Jee Young Han; Sang Youb Han; Kum Hyun Han; Hyoung Kyu Kim; Dae Ryong Cha

Visfatin (also known as pre-B cell colony-enhancing factor) is a newly discovered adipocytokine that is preferentially produced by visceral fat and regulated by cytokines promoting insulin resistance. Here we determined its renal synthesis and physiology in a genetic model of type 2 diabetes in rats. These rats had higher levels of visfatin synthesis in both glomeruli and tubulointerstitium compared to control rats. Plasma visfatin levels were significantly increased in the early stages of diabetic nephropathy and positively correlated with body weight, fasting plasma glucose, and microalbuminuria. Interestingly, visfatin synthesis was found to occur in podocytes and proximal tubular cells, as well as in adipocytes in vitro. Further, in both renal cells, visfatin synthesis was significantly increased by high glucose in the media but not by angiotensin II. Additionally, visfatin treatment induced rapid uptake of glucose and was associated with increased translocation of GLUT-1 to the cellular membrane of both renal cell types. Furthermore, visfatin induced tyrosine phosphorylation of the insulin receptor, activated downstream insulin signaling pathways such as Erk-1, Akt, and p38 MAPK, and markedly increased the levels of TGFbeta1, PAI-1, type I collagen, and MCP-1 in both renal cells. Thus, our results suggest that visfatin is produced by renal cells and has an important paracrine role in the pathogenesis of diabetic nephropathy.


Nephrology | 2009

Role of the VEGF 936 C/T polymorphism in diabetic microvascular complications in type 2 diabetic patients

Hye Won Kim; Gang Jee Ko; Young Sun Kang; Mi Hwa Lee; Hye Kyoung Song; Hyoung Kyu Kim; Dae Ryong Cha

Aim:  Vascular endothelial growth factor (VEGF) is important in the pathogenesis of diabetic microvascular complications and the genetic polymorphism of this gene may contribute to the development and progression of diabetic microvascular complications. In this study, we investigated whether a genetic polymorphism of VEGF is associated with diabetic complications.


Nephron Clinical Practice | 2010

Association between Depression Symptoms with Inflammation and Cardiovascular Risk Factors in Patients Undergoing Peritoneal Dialysis

Gang Jee Ko; Myung Gyu Kim; Young Mi Yu; Sang Kyung Jo; Won Yong Cho; Hyoung Kyu Kim

Despite medical progress, high morbidity and mortality rates, due primarily to cardiovascular diseases, have persisted in patients with end-stage renal disease (ESRD). Recently, nontraditional risk factors, such as inflammation and malnutrition, have been emphasized in the development or progression of atherosclerosis in ESRD patients. Depression, the most common psychological problem in the ESRD population, is also known to be associated with inflammation and malnutrition, suggesting a possible link between depression with inflammation and cardiovascular diseases. The purpose of this study was to investigate the relationship between depression with cardiovascular risk factors and inflammation in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Eighty-one stable CAPD patients were enrolled. Depressive symptoms were assessed with the Beck Depression Inventory. Various cardiovascular risk factors and inflammatory markers were measured. Forty-three patients had depressive symptoms (53.8%). Patients with depressive symptoms showed significantly lower levels of albumin and IL-10, but higher levels of inflammatory markers than patients without depressive symptoms. Left ventricular hypertrophy was also found more frequently and pulse wave velocity and asymmetric dimethylarginine were all significantly increased in patients with depressive symptoms. Depression in CAPD patients was associated with inflammation and cardiovascular risk factors, and might be used as a predictor of cardiovascular diseases.

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Young Joo Kwon

Soonchunhyang University Hospital

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