Mesangial 세포에 대한 고농도 포도당의 영향 및 PDGF 수용체억제제의 효과

형근영,박병현,박승택,조정구 圓光大學校 醫科學硏究所 2001 圓光醫科學 Vol.16 No.1-2

배경: 신세포의 비대를 매개하는 대표적인 성장인자들은 TGF-β외에도 IGF-1, PDGF(platelet derived growth factor, 혈소판 유래 성장인자), EGF, FGF 등이 있으며 혈관활성물질인 엔지오텐신 Ⅱ(Angiotensin Ⅱ) 등도 당뇨병성 신증 발생에 관여한다는 보고가 있다. 그중 PDGF는 강력한 mitogen으로 메산지움세포와 같은 간질(mesenchymal) 기원 세포에 대하여 강한 화학친화성(chemoattractant)을 보이며 메산지움세포의 증식이 나타나는 동물 및 사람의 사구체신염에서 발현되어, 당뇨병성 신증 발생 시 나타나는 메산지움 세포의 증식과 관련 가능성에 관심이 모아져있다. 그러나 PDCF, TGF-β 등의 사이토카인 들 사이의 작용 및 메산지움세포에 대한 영향은 배양세포의 종류 및 밀도, 처리한 사이토카인이 내인성 인지 외인성으로 투여된 것인지, 배양액 내 혈청의 존재유무, 다른 사이토카인의 활성화 여부등에 따라 결과가 다르게 보고되어 사이토카인의 작용에 복잡성이 있고 특히 메산지움 세포 증식에 미치는 TGF-β의 영향에 대한 연구는 매우 부족하고도 서로 상반된 결과를 보이고 있는 실저이다. 방법: 저자는 당뇨병성 신증의 병인 규명 및 치료에 관한 연구의 일환으로 고농도 포도당 배지에서 PDGF 수용체 억제제를 사용하여 생쥐 배양 메산지움세포에 미치는 PDGF의 영향을 알아보고 TGF-β와의 상호 연관성을 알아보고자 본 연구를 시행하였던 바 다음의 결과를 관찰하였다. 결과: 5mM 포도당 농도에 비해 10mM 및 30mM 등 고 포도당농도에서 TGF-β 처리가 지속적으로 메산지움세포 증식을 유발하여 당뇨병성 신증의 발생 및 진행에 중요한 역할을 할 것으로 생각되었다. 또한 PDGF 수용체 억제제인 suramin 을 TGF-β와 함께 처리하자 TGF-β를 단독 처리했을 때 관찰되었던 메산지움세포의 증식이 차단되었다. 결론: 당뇨병성 신증의 진행에 관여하는 성장인자들은 서로 자가분비 또는 측분비의 형태로 서로 매개 작용을 하는 것으로 보이며 고농도 포도당상태에서의 TGF-β의 메산지움 세포에 대한 작용과정에 PDGF가 매개 역할을 하고 있는 것으로 생각된다. Background : Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular elements, thickening of the glomerular and tubular basement membranes, progressive accumulation of extracellular matrix components in mesangial cells, and tubulointerstitial fibrosis. Hyperglycemia increases the level of diacylglycerol(DAG) and activates protein kinase C(PKC) in mesangial cells and other vascular tissues. PKC activation regulates a number of vascular functions such as vascular permeability, contractility, cellular proliferation, basement membrane synthesis, signal transduction mechanisms for hormones and growth factors. In addition, glomerular mesangial cells play an important role in the development of diabetic nephropathy. Mesangial cells have several functions such as contractile properties, phagocytosis of macromolecules, synthesis of matrix proteins, and production and response to growth factors like platelet derived growth factor(PDGF), transforming growth factor-β(TGF-β). Also, these growth factors play important roles in mesangial cell proliferation and pathophysiology of diabetic nephropathy. Specifically, TGF-β is a key mediator in development of diabetic nephropathy. Methods : In order to clarify the effect of high glucose concentration and the relation- ship between PDGF and TGF-β on mouse mesangial cell proliferation, hyperglycemia was induced by the addition of high glucose to medium containing mesangial cells derived from neonatal mouse. The effect of high glucose was assessed by the cell proliferation, after mesangial cells were induced with various concentrations of glucose for 48 hours. The effect of TGF-β and PDGF on cell proliferation was examined and the effect of an inhibitor of PDGF and its receptor, suramin was also examined. Results : 1. LC_50 was a concentration of 20mM glucose when mesangial cells were cultured for 48 hours. 2. Hyperglycemia decreased cell number after mesangial cells were incubated for 48 hours with media containing 20-25 mM glucose, respectively. 3. TGF-β increased cell number dose-dependently. 4. PDGF induced a significant cell proliferation, but suramin, an inhibitor of PDGF receptor decreased in cell number in dose-dependently. 5. In the cell number, suramin decreased in number of mesangial cells against TGF-β induced cell proliferation. Conclusion : High glucose induced toxic effect, so it was manifestated by decreased number of cultured mesangial cells, and PDGF receptor inhibitor decreased cell proliferation which increased by TGF-β in high glucose. This means PDGF may modulate TGF-β effect on mouse mesangial cell proliferation in high glucose concentration.

승모판 일탈증 환자에서 발생한 감염성 심내막염과 진균성 동맥류 파열에 의한 뇌졸중 2례

형근영,백승훈,임수빈,오석규,정진원,박옥규 圓光大學校 醫科學硏究所 1997 圓光醫科學 Vol.13 No.1-2

Mitral valve prolapse(MVP) is defined as displacement of some part of mitral valve into left atrium over the mitral valvular anulus during systole by numerous etiology. It is detected common in young women, and its symptom exhibits so variable from asymptomatic to fatigue, palpitation as well as autonomic nervous system symptoms. When it is complicated with mitral regurgitation, mitral valve prolapse may cause serious complications such as infective endocarditis(IE). If MVP complicates with infective endocarditis, variable neurologic complications developed relatively common (40-50%) and in case developed into mycotic aneurysm, critical complication such as subarachnoid hemorrhage(SAH) and stroke can occur. We have experienced the two cases of MVP in young women complicated with IE and mycotic aneurysm rupture causing cerebrovascular accidents(CVA). The diagnosis was confirmed by blood culture, echocardiogram, brain CT and cerebral artery angiogram. And they have the dismal outcome despite of the the meticulous medical and surgical treatments. So we suggest that MVP is a potential risk factor of CVA, especially in young patient with stroke who without definitive risk factors.

건 황색종의 가족력과 관상동맥질환을 갖는 이형집합 가족성 고 콜리스테롤혈증 1례

백승훈,형근영,김경년,조정구,이경근 圓光大學校 醫科學硏究所 1997 圓光醫科學 Vol.13 No.1-2

Familial hypercholesterolemia is a common autosomal dominant disorder with serious health consequences such as the coronary heart disease, in western area affecting approximately 1 in 500 persons in the heterozygous form, is caused by a mutation in the gene for the LDL(low density lipoprotein) receptor. A-45-years old male came to the hospital because of tendon xanthomas on both elbows, knees, and ankles. He also has retrosternal chest pain intermittently since 5 years ago. 4 kindreds of the patient have tendon xanthomas according to autosomal dominant inheritance. Serum levels of total cholesterol and triglyceride were 359 ㎎/dL, 103 ㎎/dL respectively. Lipoprotein electrophoresis showed type Ⅱa pattern. Treadmill exercise test revealed angina pectoris. The case of familial hypercholesterolemia who has familial inheritance of tendon xanthoma is rarely reported in Korea. We report this case with a review of the related literature

신경성장인자(神經成長因子)로서의 약류별(藥類別) 한약제(韓藥劑)가 척수(脊髓) 운동신경세포(運動神經細胞)의 손상(損傷)에 미치는 효능(效能) 및 기전(機轉)에 관(關)한 비교(比較) 연구(硏究)

박승택,윤향석,형근영,조정구,이강창,김원신,김형민,전병훈,윤용갑,Park Seung-Taeck,Yoon Hyang-Suk,Hyoung Keon-Young,Cho Chung-Gu,Lee Kang-Chang,Kim Won-Shin,Kim Hyung-Min,Jeon Byung-Hoon,Yun Young-Gap 대한한의학방제학회 1999 大韓韓醫學方劑學會誌 Vol.7 No.1

In order to eludidate the mechanism of oxidative stress in cultured spinal motor neurons damaged by oxygen free radicals, cytoxicity was assesed by MTT assay and NR assay after spinal motor neurons from mouse were cultured in media containing various concentrations of xanthine oxidase(XO) and hypoxanthine(HX) for 3 hours. In addition, neuroprotective effects of several herb extracts on oxidant-induced neurotoxicity were examined in these cultures, compared with nerve growth factors such as basic fibroblast growth factor(bFGF). XO/HX decreased cell viability in dose- and time dependent manners on cultured mouse spinal motor neurons, and MTT50 and NR50 values were measured at 20mU/ml XO and 0.1mM HX for 3 hours in these cultures. bFGF significantlt increased cell viability. In neuroprotective of herb extracts, Epimedium Koreanum Nakai(EK) and Alpinia oxphylla Mig(IJI) was very effective in the prevention of the neurotoxicity induced by XO/HX in cultured mouse spinal motor neurons. From the above results, it is suggested that XO/HX shows toxic effect in cultured mouse spinal motor neurons and selective herb extracts such as Epimedium Koreanum Nakai(EK) and Alpinia oxphylla Mig(IJI) were very effective in the increase of cell viability against the neurotoxicity induced by oxygen radicals in these cultures.

칼만증후군(Kallmann's Syndrome) 1례

김용성,백승훈,유경훈,구기선,형근영,김경년,조정구 圓光大學校 醫科學硏究所 1997 圓光醫科學 Vol.13 No.1-2

Kallmann's syndrome is the most common form of isolated gonadotropin deficiency, characterized by hypogonadotropic hypogonadism due to GnRH deficiency, delayed puberty and smelling difficulty. It occurs sporadic or familial pattern, and the mode of inheritence has not been fully documented. The defect in patient of Kallmann's syndrome occurs at suprapituitary level involving mechanism that regulate GnRH synthesis or release, so this syndrome classified as a secondary hypogonadotropic hypogonadism. The gonadotropin or pulsatile GnRH administration enable successful stimulation of spermatogenesis and fertility. We have experienced 1 patient with Kallmann's syndrome and presented with the review of the literature.

신경성장인자가 고혈당 환경에서 배양된 슈반세포의 변화에 미치는 영향

김경희,장근영,백승훈,형근영,조정구 圓光大學校 醫科學硏究所 1999 圓光醫科學 Vol.15 No.2

Background: Nerve growth factor(NGF) is produced in tissues innervated by its responsive neurons. In the peripheral nervous system, NGF messenger RNA(mRNA) is produced in target fields of small pain and temperature- mediating dorsal root ganglia(DRG) sensory neurons and sympathetic neurons. NGF receptors are expressed in these neurons. NGF has been shown to promote their survival differentiation, and maitenance. But the mechanism of neuronal damage in diabetes and the effect of NGF on diabetic neuropathy are not clear. Methods: In order to clarify the neurotoxic effect of hypergiycemia, the hyperglycemia-induced cytotoxic effects were evaluated by MTT assay on cultured rat Schwann cells which were grown with media containing concentrations of high glucose for inducing hyperglycemic condition. And also the neuroprotective effect of nerve growth factor(NGF) against hyperglycemia- induced neurotoxicity were also examined. Results: 1. MTT50 value was at concentration of 25mM glucose after Schwann cells were exposed to various concentrations of glucose for 72 hours. 2. Cell viability of cultured rat Schwann cells treated with hyperglycemic media made with 25-35mM glucose was markedly decreased in a dose-dependent manner compared with control medium(normoglycemic medium) containing concentration of 5.5mM glucose, While cell number did not show a dosedependent decrease. 3. Cultured Schwann cells exposed to hyperglycemic medium made with 25mM glucose for 72 hours did not show any morphological change as well as decrease of cell number. 4. Pretreatment of 10ng/㎖ NGF for 2 hours increased remarkably the cell viability of cultured Schwann cells exposed to hyperglycemic medium made with 25mM glucose for 72 hours. Conclusions: From the above results, it is suggested that hyperglycemic condition induces the decrease of cell viability on cultured Schwann cells of rat. But it did not show the decrease of cell number and morphological change. And also selective neurotrophic factors such as NGF are very effective in preventing dysfunction of cells induced by glucose toxicity in hyperglycemic condition.

고혈당 환경에서 배양된 백서 슈반세포에 미치는 신경성장인자의 영향

김경희,백승훈,장근영,조정구,형근영 대한당뇨병학회 2000 Diabetes and Metabolism Journal Vol.24 No.1

Background: Nerve growth factor (NGF) is produced in tissues innervated by its responsive neurons. In the peripheral nervous system, NGF messenger RNA (mRNA) is produced in target fields of small pain and temperature-mediating dorsal root ganglia (DRG) sensory neurons and sympathetic neurons. NGF receptors are expressed in these neurons, and NGF has been shown to promote their survival, differentiation, as well as maintenance. However, the mechanism of neuronal damage in diabetes and the effect of NGF on diabetic neuropathy are unclear. Methods: In order to clarify the effect of hyperglycemia, the hyperglycemiainduced cytotoxic effects were evaluated by MTT assay on cultured rat Schwann cells. Schwann cells were grown with media containing concentrations of high glucose for inducing hyperglycemic condition. The neuroprotective effect of nerve growth factor (NGF) against hyperglycemia-induced Schwann cell changes were also examined. Result: 1. MMT50 value was at concentration of 25 mM glucose after 72 hours. 2. Cell viability of cultured rat Schwann cells treated with hyperglycemic media made with 25∼35 mM glucose was markedly decreased in a dose-dependent manner when compared with control medium (normoglycemic medium) containing concentration of 5.5 mM glucose, While cell number did not show a dosedependent decrease. 3. Cultured Schwann cells exposed to hyperglycemic medium made with 25mM glucose for 72 hours did not show any morphological change as well as decrease of cell number. 4. Pretreatment of 10 ng/mL NGF for 2 hours increased remarkably the cell viability of cultured Schwann cells exposed to hyperglycemic medium (25 mM glucose for 72 hours). Conclusions: The results from this study suggested that hyperglycemic condition induces the decrease of cell viability on cultured Schwann cells of rat. But it did not show the decrease of cell number and morphological change. The selective neurotrophic factors such as NGF are very effective in preventing dysfunction of cells induced by hyperglycemic condition.

부신피질호르몬과 성장호르몬의 증가를 동반한 제2형 다발성 내분비선종(MEN Ⅱa) 1례

구기선,이재홍,유경훈,백승훈,형근영,조정구,이경근 圓光大學校 醫科學硏究所 1997 圓光醫科學 Vol.13 No.1-2

Multiple endocrine neoplasia type 2a(MEN 2a) is autosomal dominant disorders arising from mutations on chromosome 10q11.2 in the region of the RET proto-oncogenes which encodes a receptor tyrosine kinase. The features of MEN 2a include pheochromocytoma (in about 40% of gene carriers), medullary thyroid carcinoma, primary hyperparathyroidism (adenoma or hyperplasia). Carriers of MEN 2a genes can best be identified by serial measurement of stimulated blood calcitonin levels. Recent advances in mapping the MEN 2a gene now allows direct genetic testing, replacing calcitonin testing as a screening tool. We experienced a case of MEN 2a in a 35-year-old female patient. She underwent total thyroidectomy nine years ago due to medullary thyroid carcinoma. The pheochromocytoma, which was detected by biochemical tests, CT scan and ^131I-MIBG scan was successfully removed by bilateral adrenalectomy with preoperative alpha and beta adrenergic blockades. Her blood pressure and blood sugar level became normal after operation.

성인에서 고인슐린혈증성 저혈당을 보인 췌장내의 미만성 Nesidioblastosis 1예

조정구,채권묵,서검석,윤기중,양광수,이승하,형근영,신봉주 대한내분비학회 1996 Endocrinology and metabolism Vol.11 No.2

Nesidioblastosis is a term that describes multifocal hyperplasia of all panereatic cell components and is characterized primarily by their disorganization and proliferation throughout the entire pancreas. Adult onset nesidioblastosis is an extremely rare entity associated with hypersecretion of insulin. The authors have recently experienced a case of nesidioblastosis in an adult. A 41-year old man was admitted due to intermittent hypoglycemic symptoms, that had been relieved by carbohydrate ingestion. Hyperinsulinemic hypoglycemia was documented during prolonged fast. Under the presumptive diagnosis of insulinoma, abdominal CT, celiac angiogram and percutaneous transhepatic portal venous sampling were done but we could not find any definitive mass. Eight-five percent of the pancreas was removed. Pathologic examination of the resected pancreas revealed irregularly sized islets and scattering of small endocrine cell clusters throughout the acinar tissue and ductuloinsular complex(1 Kor Soc Endocrinol 11:247~253, 1996).

당뇨병성 케톤산증에 병발한 횡문근융해증 1예

장근영,이명수,최용원,최경숙,김상욱,김기훈,박병현,형근영,김경년,정병화,조정구 대한당뇨병학회 2000 임상당뇨병 Vol.1 No.1

당뇨병성 케톤산증이나 비삼투압성 비케톤성 혼수환자에서 횡문근융해에 의한 급성신부전이 동반될 수 있으며 이러한 기전은 확실히 밝혀져 있지 않다. 저자들은 당뇨병성 케톤산증 환자에서 횡문근융해증 및 근색소뇨증, 급성신부전을 보인 1예를 경험하였기에 문헌고찰과 함께 보고하는 바이다. Since osmotic diuresis, which is provoked by a high renal glucose load, prevents the development of acute tubular necrosis; there have been a few case reports connecting diabetic ketoacidosis with acute renal failure, secondary to rhabdomyolysis. Rhabdomyolysis is a clinical and biochemical syndrome, resulting from skeletal muscle injury with release of muscle contents, specifically myoglobin into the plasma and it has been implicated as a major cause of acute renal failure. Rhabdomyolysis is diagnosed in the presence of myoglobinuria and raised level of serum creatinine phosphokinase (CPK). We report a case of diabetic ketoacidosis which developed acute renal failure secondary to rhabdomyolysis and myoglobinuria with review of the literature. A 67-year-old man suffering from somnolence was admitted to our hospital. He had had coughing, sputum, chills for 7 days prior to the onset of somnolence. He was a type 2 diabetic patient and had been omitting oral hypoglycemic agent for two months. Laboratory data an admission reveled elevated serum levels of glucose (>27 mmol/L), myoglobin (>500 ng/㎗), creatinine phosphokinase (2,156IU/L), lactate dehydrogenase (1,679 IU/L), blood urea nitrogen (12.4 mmol/L) and creatinine (247 mmol/L). Ketone and myoglobin (75 ng/㎗) was defected in urine. Arterial blood gas analysis reveled pH 7.104, PCO₂ 15 mmHg, PO₂ 108.3 mmHg, HCO₃ 4.8 mmol/L, Chest film showed pneumonic consolidation on right lower lung. Treatment with subcutaneous insulin and intravenous administration of electrolyte fluid and the systemic antiobiotics was begun immediately. After initiation of treatment, there was increase in serum creatinine 0(707 mmol/L), blood urea nitrogen (56.7 mmol/L), and anuria w as observed. Despite of care, he died.