PROTECYIVE ERRECT OF CAPROPRIL ON EXPERIMENTAL DLABETIC ALBUMINUPIA

Ha, Hunjoo,Yoon, Sucr Jong,Kim, Kyng Hwan 대한신장학회 1993 Kidney Research and Clinical Practice Vol.12 No.2

Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-β1-induced renal injury

Hunjoo, Ha,Hyunjin, Noh,Eun Young, Oh,Ji Yeon, Seo,Mi Ra, Yu,Young Ok, Kim,Hi Buhl, Lee 이화여자대학교 약학연구소 2010 藥學硏究論文集 Vol.- No.20

Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-β1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-β1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-β1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and α-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcystein, almost completely reduced TGF-β1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-β1-induced activation of HDAC-2.

Role of reactive oxygen species in the pathogenesis of diabetic nephropathy

Ha, Hunjoo,Hwang, In-A,Park, Jong Hee,Lee, Hi Bahl 이화여자대학교 약학연구소 2009 藥學硏究論文集 Vol.- No.19

There is an increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. Oxidative stress is increased in diabetes and the overproduction of ROS in diabetes is a direct consequence of hyperglycemia. Various types of vascular cells including renal cells are able to produce ROS under hyperglycemic condition. Both NADPH oxidase and mitochondrial electron gradient play roles in hyperglycemia-induced ROS generation. In addition to their ability to directly inflict macromolecular damage, ROS can function as signaling molecules. ROS mediate hyperglycemia-induced activation of signal transduction cascades and transcription factors leading to transcriptional activation of pro fibrotic genes in the kidney. Furthermore, ROS-activated signaling molecules generate and signal through ROS and thus ROS act as a signal amplifier. Intensive glycemic control and inhibition of angiotensin II delay the onset and progression of diabetic nephropathy, in part, through prevention of overproduction of ROS. Conventional and catalytic antioxidants have been shown to prevent or delay the onset of diabetic nephropathy. Combination of strategies to prevent overproduction of ROS and to increase the removal of preformed ROS may prove to be effective in preventing the development and progression of diabetic nephropathy.

Renoprotective antioxidant effect of alagebrium in experimental diabetes

Hunjoo, Ha,Jehyun, Park,MinKyung, Kwon,Joo Young, Huh,Won Jun, Choi,Lak Shin, Jeong,Ryoji, Nagai,Wan Young, Kim,Geun Taek, Lee,Hi Bahl, Lee 이화여자대학교 약학연구소 2012 藥學硏究論文集 Vol.- No.22

BACKGROUND: Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H(2)O(2) and a test tube. METHODS: ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (D(ALA)E) mice or for 4 weeks to 16-week-old db/db mice (D(ALA)L). Oxidative stress markers (nitrotyrosine accumulation, expression and translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, cellular DCF-DA fluorescence) together with urinary albumin excretion and histological changes including mesangial expansion were measured. The concentration of H(2)O(2) in the presence and absence of ALA was measured by iodometric analysis in a test tube. RESULTS: ALA significantly reduced not only urinary albumin excretion and renal pathological changes but also accumulation of pentosidine and nitrotyrosine and expression of NADPH oxidase subunits in db/db mice regardless of treatment protocol. In mesangial cells, ALA effectively prevented not only high glucose- but also H(2)O(2)-induced membrane translocation of NADPH oxidase subunit (p47 phox, p67 phox and rac1) and protein kinase C isoform (α, βI and βII) and Nox4 messenger RNA expression concomitant with cellular reactive oxygen species. Furthermore, ALA directly decreased H(2)O(2) in a test tube. CONCLUSION: ALA has both direct and indirect antioxidant effects that may play important roles in ALA's renoprotective effect in diabetic kidneys.

Effect of Piogiitazone on Cerebrovascular Blood Flowin Type 2 Diabetic Patients

HA Hunjoo,AHN Chul Woo,GWAK Hye-Sun,PARK Jong Sook,LEE Yoo Jeong 大韓藥學會 2005 大韓藥學會 總會 및 學術大會 Vol.2005 No.2

Amelioration of diabetic microalbuminuria and lipid peroxidation by captopril

Ha, HunJoo,Kim, Kyung Hwan Yonsei University, College of Medicine 1992 Yonsei medical journal Vol.33 No.3

Protective Effect fo Captopril on Experimental Diabetic Albumlinuria

( Hunjoo Ha,Suck Jong Yoon,Kyung Hwan Kim ) 대한신장학회 1993 학술대회및초록집 Vol.12 No.2

ROLE OF KIDNEY AND LIVER IN THE RENOTROPIC ACRIVITY AFTER UNINERHRECTOMY IN RATS

Ha, Hunjoo,Yoon, Sucr Jong,Kim, Kyng Hwan 대한신장학회 1993 Kidney Research and Clinical Practice Vol.12 No.2

The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases

Ha, Hunjoo,Oh, Eun Y.,Lee, Hi B. Springer Science and Business Media LLC 2009 Nature reviews. Nephrology Vol.5 No.4

<P>The 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) is the major physiological inhibitor of tissue-type and urokinase-type plasminogen activator. These two molecules convert inactive plasminogen into its fibrin-degrading form, plasmin. Plasma and tissue concentrations of PAI-1 are extremely low under normal circumstances but increase under pathologic conditions. This increase is mediated by many factors, including reactive oxygen species. Increased PAI-1 activity is associated with an increased risk of ischemic cardiovascular events and tissue fibrosis. Whereas the antifibrinolytic property of PAI-1 derives mainly from its inhibition of serine proteases, its profibrotic actions seem to derive from a capacity to stimulate interstitial macrophage recruitment and increase transcription of profibrotic genes, as well as from inhibition of serine proteases. Despite studies in mice that lack or overexpress PAI-1, the biological effects of this molecule in humans remain incompletely understood because of the complexity of the PAI-1-plasminogen-activator-plasmin system. The cardioprotective and renoprotective properties of some currently available drugs might be attributable in part to inhibition of PAI-1. The development of an orally active, high-affinity PAI-1 inhibitor will provide a potentially important pharmacological tool for further investigation of the role of PAI-1 and might offer a novel therapeutic strategy in renal and cardiovascular diseases.</P>

Carvedilol이 배양된 사람 혈관 평활근 세포의 증식과 그에 관여하는 세포내 신호전달계에 미치는 영향

박제현,하헌주,오재원,김명수,서지연,김혜진,박기일,김유선 대한혈관외과학회 2002 Vascular Specialist International Vol.18 No.1

장기이식 후 만성거부반응이나 혈관손상 후 재협착 등의 복원과정(remodeling) 그리고 동맥경화증의 병태생리는 비슷하여 물리적 손상이나 면역학적 또는 비면역학적 원인에 의해서 혈관내피의 손상이 발생하면 혈관 평활근 세포의 증식과 이동이 항진되며 세포 외 기질이 과다 생산되어 혈관의 내막증식과 섬유화가 초래된다. 이러한 병태 생리과정을 효과적으로 제어하는 방법은 매우 제한적으로 여러 약제를 사용하여 다양한 cytokine과 성장인자의 생성과 빈혈을 억제함으로써 혈관 병변과 재협착을 억제하고자 하는 시도가 있어왔으나 임상에서 사용할 정도로 그 효과가 확연하게 밝혀진 제제는 아직까지 없다)1-3). 연구자들은 최근에 항고혈압제로 사용중인 carvedilol 제제가 백서의 혈관 평활근세포의 증식과 이동을 효과적으로 억제함을 관찰하여 보고한 바 있다(4-5). 아드레날린성 β억제제로 개발된 carvedilol은 아드레날린성 α억제제 및 항산화제 등 다양한 기능을 가진 제제로서(6) 다양한 혈관 병변을 가진 환자나 신장이식환자에서 항고혈압제제의 복용이 필요한 상황을 고려해 보면 carvedilol의 투여는 혈압 강하효과 이외에도 혈관병변의 예방과 치료에 효과가 있을 것으로 사료된다. 세포의 성장과 증식은 이를 촉진하거나 억제하는 유전자 발현과 단백질 합성에 의해 이루어지며 정상 생리 상태에서는 유기적으로 잘 조절되는 신호변환기전에 의해서 조절된다. 성장인자는 세포막에 있는 수용체와 결합하여 그 수용체를 활성화시킨 후 신호변환기전을 경유하여 핵내의 유전자 발현을 조절한다. 특히, mitogen-activated protein kinases (MAPK)는 세포질에 존재하는 단백질의 인산화 효소로서 extra-cellular-regulatory protein kinase (ERK), c-jun N-terminal kinase (JNK), p38 MAPK의 세 가지 형태가 있으며, 각각 세포외부의 각종 자극 인자들에 의해 연속적으로 활성화되어 전사조절인자를 활성화한다(7-11). 최근의 보고에 따르면 MAPK나 전사조절인자의 활성조절에는 활성산소족(reactive oxygen species)과 이들에 의해 유도되는 세포내 산화-환원 상태의 변화가 상당부분 관여하는 것으로 알려져 있다(7,12,13). 따라서, 본 연구자들은 carvedilol 제제가 인체 유래 혈관 평활근세포의 증식에 미치는 영향과 이에 관여하는 신호 전달계 중 활성산소족생성과 MAPK의 활성화에 미치는 영향을 규명하기 위하여 본 실험을 실시하였다. Purpose: Vascular smooth muscle cells (VSMSs) migration and proliferation play important roles in transplant vascular sclerosis and restenosis afer balloon vascular injury. The antiproliterative and anti-migratory effects of carvedilol (CA), a unique α-and β-blocking anti-hypertensive drug, on the VSMCs were confirmed previously. Since reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPK) family play important roles in proliferation of VSMCs, the present study examined the effects of CA on intracellular ROS generation, activation of ERK 1/2 and p38 MAPK, and proliferation of VSMCs were cultured with RPMI-1640 containing 10% fetal bovine serum. Near confluent VSMCs were incubated with serum-free media for 48 hours to arrest and synchronize the cell growth. CA was administered 1 hour before the addition of PDGF. 5-(and-6)-chloromethy-2',7'-dichlorodihydrofluo-rescein (DCF)-sensitive intracellular ROS was detected by FACS. Activations of ERK 1/2 and p38 MAPK were measured by Western blot analysis, Proliferation of VSMCs was assessed by [^3H]-thymidine incorporation. Results: PDGF at 10 ??/㎖, which induced human VSMCs proliferation, rapidly increased intracellular ROS by 1.6-fold (P < 0.01), ERK 1/2 activation by 2.1-fold (P < 0.01), and p38 MAPK activation by 1.9-fold (P < 0.01), respectively, as compared to the control. CA 1 and 10μM effectively inhibited PDGF-induced human VSMCs proliferation. CA also effectively inhibited PDGF-induced intracellular