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1 대한내과학회지 : 제 77 권제 6 호 2009 특집 (Special Review) - 당뇨병성신부전의관리와최신치료 당뇨병성신증의병태생리 연세대학교의과대학내과학교실 박정탁 강신욱 Pathogenesis of diabetic nephropathy Jung Tak Park, M.D., and Shin-Wook Kang, M.D. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Diabetic nephropathy, the leading cause of end stage renal disease in many countries, is pathologically characterized by glomerular and tubular hypertrophy, extracellular matrix accumulation, inflammatory cell infiltration, and podocytopenia associated with foot process effacement, which eventually results in glomerulosclerosis and tubular atrophy. The pathogenesis of diabetic nephropathy comprises both metabolic and hemodynamic factors related to diabetes. Hemodynamic factors include intraglomerular hypertension which is associated with the activation of both systemic and local renin-angiotensin system. Hyperglycemia per se, advanced glycation end-products and glucose-dependent aldose reductase pathways, as metabolic factors, is also known to contribute to the development and progression of diabetic nephropathy. All of these factors induce various cytokines and activate intracellular signal transduction pathways such as protein kinase C and mitogen-activated protein kinase, ultimately leading to diabetic nephropathy. (Korean J Med 77: , 2009) Key Words: Diabetic nephropathy; Advanced glycated end-products; Renin-angiotensin system; Reactive oxygen species 서론당뇨병성신증은최근들어말기신질환의가장흔한원인질환으로대두되었다 1,2). 당뇨병성신증은초기에고혈당의발현과함께사구체여과율의증가를동반하며, 임상에서신장내과의사는주로 30~300 mg/day의미세알부민뇨를동반한당뇨병성신증환자로처음접하게된다. 제1형당뇨병의경우, 미세알부민뇨증환자에서약 10년내에현성단백뇨가발생하게되는경우가많으며, 제2형당뇨병에서도 20~40% 의환자에서는당뇨병성신증과관련된단백뇨가발생하게된다. 미세알부민뇨시기이후사구체여과율의감소 와함께단백뇨배설의증가가지속된다 3). 병리학적으로는사구체및세뇨관의비후, 메산지움 (mesangium) 과세뇨관- 간질 (tubuloinerstitium) 에세포외기질 (extracellular matrix) 의축적그리고사구체기저막 (glomerualr basement membrane) 과신세뇨관기저막 (tubular basement membrane) 의비후가일어난다. 또한, 사구체와세뇨관-간질에염증세포의침윤이나타나며, 사구체내족세포 (podocyte) 수의감소와족돌기의융합 (foot process effacement) 이일어나며, 이러한변화의지속적인진행으로인하여궁극적으로는사구체경화 (glomerulosclerosis) 및신세뇨관위축 (tubular atrophy) 이발생하게된다 4). * This work was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A084001)

2 - Jung Tak Park, et al. Pathogenesis of diabetic nephropathy - 당뇨병성신증에서동반되는이러한다양한변화의병태생리는아직완전히규명되어있지는않으나, 혈역학적요인과당뇨병과동반되는여러대사적요인의상호작용에의하여일어나는것으로알려져있다 5). 혈역학적인측면에서당뇨병은사구체내고혈압을야기시킬뿐만아니라당뇨병의유병기간이길어짐에따라고혈압이동반되는경우가많으며, 이러한변화에는 renin-angiotensin-aldosterone system (RAS), endothelin 그리고 urotensin의활성화가관여하는것으로보고되고있다. 고혈당은신장을구성하는여러세포에서대사와관련된신호전달체계를활성화하는것으로알려져있으며, 이들신호전달체계의활성화는산화성스트레스 (oxidative stress) 와 advanced glycated end-product (AGE) 의축적과밀접한연관이있는것으로알려져있다. 본논문에서는당뇨병성신증의발생및진행에관여하는다양한혈역학적요인과대사성요인그리고이로인하여활성화되는신호전달체계및각종 cytokine에대하여간단히기술하였다. 혈역학적요인당뇨병성신증의초기소견인사구체여과율의증가는사구체의수입관 (afferent arteriole) 과수출관 (efferent arteriole) 의저항감소에의하여나타난다. 이중에서도수출관의저항이수입관의저항에비하여상대적으로더감소되어사구체내혈압이상승하게되는데, 이러한사구체내혈압증가에는 RAS 뿐만아니라 prostanoid, nitric oxide 그리고 vascular endothelial growth factor (VEGF) 가관여하는것으로알려져있다. 이들요인에의한사구체내혈역학적변화에의하여사구체에서의알부민배설량이증가되게되며 6), 이와더불어형성된 mechanical strain 에의하여신장내에서국소적으로생성이증가된각종 cytokine 과성장인자 (growth factor) 가메산지움세포 (mesangial cells) 의증식, 사구체기저막의증가, 그리고족세포손상을야기시킨다 7). 1. Renin-angiotensin system (RAS) 수많은연구를통하여 angiotensin-converting enzyme (ACE) 억제제는환자및실험동물에서당뇨병성신증의발생을억제시킬뿐만아니라진행을지연시키는것으로알려져있는데, 이러한연구결과를토대로 RAS가당뇨병성신증의병태생리와밀접한관련이있을것으로여겨졌다. 또한최근에는 circulating RAS 와더불어족세포및세뇨관세포를포함한신장의각종구성세포에서 RAS의모든구성성분이존재할뿐만아니라당뇨조건하에서국소적 RAS의활성화가일어나는것으로보고됨에따라당뇨병성신증의병태생리적측면에서 RAS의역할이더욱주목을받게되었다 8,9). 또한, micropuncture 연구에의하면, 당뇨사구체내압력이증가되어있으며이렇게증가된사구체내압력은당뇨병성신증의진행과밀접한관련이있으며 10), ACE 억제제나 angiotensin II 제1형수용체차단제 (ARB) 를사용할경우사구체내고혈압뿐만아니라조직학적변화가호전되는것으로미루어보아사구체내고혈압의발생에 angiotensin II가중심적인역할을하는것으로생각되어지고있다 11). Angiotensin II는혈역학적인영향이외에도당뇨병성신증의발생및진행과관련하여여러비혈역학적인작용도하는것으로알려져있는데, 이중에서도섬유화 cytokine인 TGF-β를통하여세포외기질의생성을증가시키며 12), 세포내매개자 (intracellular mediator) 인 protein kinase C (PKC) 13) 나 nuclear factor κ-b (NFκ-B) 와같은전사인자 (transcription factor) 의발현에직접적인영향을미치는것으로보고되고있다 14). 또한, angiotensin II는다양한경로를통하여세포증식, 세포비후그리고세포사멸을일으키는것으로알려져있으며 15), 특히 angiotensin II의작용을억제할경우족세포및당뇨사구체내의 cyclin dependent kinase inhibitor인 p27 kip1 의발현의감소와더불어족세포및사구체비후가호전되는것으로보고되었다 ( 표 1) 16). Table 1. Effects of angiotensin II in diabetic nephropathy Hemodynamic Effects Systemic hypertension Systemic and renal vasoconstriction Increased glomerular capillary pressure and permeability Mesangial cell contraction leading to reduction in filtration surface area ECM, exctracellular matrix; VEGF, vascular endothelial growth factor Non-Hemodynamic Effects Induction of renal hypertrophy and cell proliferation Stimulation of ECM synthesis Inhibition of ECM degradation Stimulation of cytokine (e.g., TGF-β, VEGF, endothelin) production Stimulation of superoxide production

3 - 대한내과학회지 : 제 77 권제 6 호통권제 592 호 Figure 1. Metabolic factors involved in the pathogenesis of diabetic nephropathy. AGE, advanced glycation end product; PKC, protein kinase C; DAG, diacylglycerol; cpla2, phospholipase A2, Na-K-ATPase, sodium-potassium ATPase. 대사성요인 1. Advanced glycation end-product (AGE) 당뇨유병기간이길어짐에따라포도당은혈중또는조직내아미노산과결합하게되는데, 초기에는비효소적결합을통하여 glycated Schiff base를형성하게되며이후에는보다안정적인 Amadori product가형성되는데, 이생산물의 cross-linking을통하여비가역적인 AGE가생성된다 ( 그림 1) 17). AGE는직접적으로세포에작용하여각종 cytokine, 호르몬그리고활성산소 (free radical) 의생성을유도시키며, 이결과세포비후, 염증세포의침윤그리고세포외기질의축적이일어나게된다. 당뇨병환자에서혈중 AGE의농도가증가되어있을뿐만아니라 18), 당뇨사구체기저막에 AGE 및 AGE의수용체 (RAGE) 의발현이증가되어있다는보고들로미루어보아고혈당자체이외에도 AGE가당뇨병성신증의발생및진행과직접적이고도밀접한연관이있을것으로생각되고있다 19). 당뇨병성신증의병태생리에서 AGE는크게수용체비의존적과수용체의존적경로를통하여영향을나타내는것으로알려져있다. 수용체비의존적면에서보면, AGE는세포 기저막의세포외기질단백과교차결합을함으로써정상적인세포외기질의작용을방해할뿐만아니라세포성장과기능에도영향을미치게된다 20). RAGE는대표적인 AGE 수용체인데, RAGE와 AGE의결합에의하여세포내 PKC 및 mitogen-activated protein kinase (MAPK) 등의신호전달체계의활성화, 활성산소종 (reactive oxygen species, ROS) 의증가, 그리고 NF-kB 등의전사인자의활성화가일어나게된다 21). 또한, RAGE 과발현백서에서당뇨를유발시킨경우대조군당뇨백서에비하여단백뇨의배설이더증가되었으며 22), 메산지움세포의증식과더불어사구체경화가더심하였지만 RAGE에대한 neutralizing antibody 투여로조직학적병변이호전되었다는보고로미루어보아당뇨병성신증의발생및진행에 AGE가수용체비의존적뿐만아니라수용체의존적으로도작용함을알수있다 23). 2. Aldose reductase/polyol pathway 포도당은 polyol pathway를통하여 nicotinamide adenine dinucleotide phosphate (NADPH) 의존효소인 aldose reductase 에의하여 sorbitol 로전환되며, sorbitol의축적은세포내 myoinositol을감소시키고 Na + /K + ATPase 의활성도를감소시켜 NADPH와 NAD + 의과사용으로인하여세포내산화- 환원

4 - 박정탁외 1 인. 당뇨병성신증의병태생리 - 작용의변화를초래하게된다 ( 그림 1) 24). 당뇨병성신증에서 polyol pathway 의역할은 aldose reductase의억제를통한연구들에서밝혀진바가있는데, 고포도당하에서배양한메산지움세포에서 aldose reductase 를억제하였을경우 PKC의활성화가감소되었으며 25), 실험적당뇨백서에 aldose reductase 억제제를투여하였을경우에단백뇨의배설이감소되었다는보고가있다 26). 그러나임상에서당뇨병성신증환자를대상으로 aldose reductase 억제제를사용한결과과여과 (hyperfilteration) 는의미있게억제된반면에당뇨병성신증의진행에는의의있는효과가없었던것으로보고되어있어치료제로서의가능성에대하여서는향후좀더많은연구가필요할것으로사료된다 27,28). 3. 활성산소종산화성스트레스에의하여생성되는 ROS는당뇨합병증과밀접한연관인자로알려져있다 29). 일반적으로세포내대사를통하여생성된 ROS는다수의항산화효소 (antioxidant enzyme) 와 free radical scavenging system에의하여균형을유지하게되는데, 만성적고혈당상태에서는이균형이깨지게되어 ROS 과생산현상이나타나게되며 30), 이러한현상에는 NADPH oxidase 와 mitochondrial electron gradient가관여하는것으로되어있다. 과생산된 ROS는세포막지질의 peroxidation, 단백의산화그리고 DNA의손상을초래하는등의직접적인작용이외에도세포내에서 signaling molecule 로도작용하게되는데 31), ROS 에의하여활성화된신호전달체계는신장내에서섬유화와관련된유전자의전사를증가시키는것으로알려져있다 32). 실제로 angiotensin II의억제와고혈당의조절을통하여신장내 ROS의생성이감소되며 33), 실험적당뇨동물모델에서다양한항산화제투여로인하여당뇨병성신증의진행이억제되었다는여러연구결과들은산화성스트레스가당뇨병성신증의진행에중요한요소임을뒷받침하고있다 34). 세포내매개자 (Intracellular mediator) 1. Protein kinase C PKC는당뇨병성신증을포함한당뇨합병증의진행에매우중요한역할을하는매개체로알려져있다 35). 당뇨병성신증에대한초기세포연구를보면, 고포도당으로자극한메산지움배양세포에서 PKC를활성화시키는 phorbol ester 투여로세포외기질의생성이더증가되었으며, 반대로 PKC 의활성을억제시켰을경우에는고포도당에의한변화가억제되는것으로보고되었다 36). 만성적인고혈당자극에의하여생성된 dialcylglycerol (DAG), ROS 그리고 AGE 등은세포막에직접작용하여 phospholipase C의활성화를유도하게되며, 이로인하여세포내의 PKC가활성화된다 37,38). PKC는세포내에서 nitric oxide 의생성을감소시킬뿐만아니라 endothelin-1와 VEGF의생성을증가시키는데, 이로인하여사구체내고혈압과투과성증가와더불어세포외기질단백의축적이야기된다. 또한, NF-κB 와같은전사인자와 plasminogen activator inhibitor (PAI)-1을활성화시켜조직내의염증반응과혈관손상을진행시키며 37), 당뇨병성신증의병태에중요한역할을하는 MAPK 의 threonine, thyrosine residue를인산화시키는역할도하는것으로알려져있다 39). PKC의활성은이상에기술한바와같이당뇨에의한손상을진행시키는다양한기전을동시에조절하는역할을하기때문에당뇨병성신증의발생및진행에매우중심적인역할을할것으로간주되고있다. 2. Mitogen-activated protein kinase MAPK 는세포외자극을세포내로전달하는중심적인신호전달체계중의하나이다. MAPK는크게 extracellular signal-regulated kinase (ERK) family, c-jun N-terminal kinase, 그리고 p38 MAPK 로분류되는데, 이의활성화는당뇨병성신증에서세포증식, 분화그리고세포사멸과깊은연관이있는것으로알려져있다. 특히 MAPK 중에서 p38 MAPK 는각종신장세포에서고포도당에의해서활성화되며, 초기당뇨사구체에서도 p38 MAPK 의활성이증가되어있는것으로보고된바있다 40). 당뇨조건하에서 MAPK 는 AGE와 polyol 등에의해서도활성화되는것으로알려져있으며 41), 고포도당에의한 angiotensinogen의전사, TGF-β signaling pathway의활성화그리고 prosclerotic cytokine의발현등에의한세포외기질의축적도 MAPK 의활성과관련이있는것으로알려져있다 42,43). 최근에는 p38 MAPK 의활성을억제하였을경우고포도당으로자극한메산지움세포와실험적당뇨사구체내세포외기질의생성및세포사멸이감소되었다는보고 44) 는당뇨병성신증의병태생리에 MAPK 의역할을시사한다. 3. Nuclear factor-κb (NF-κB) NF-κB 는각종 cytokine, adhesion molecule 그리고 NO synthase 등의유전자발현에관여하는전사인자이다. NF-κB 는

5 - The Korean Journal of Medicine: Vol. 77, No. 6, 고포도당과 ROS 등의다양한자극에의하여활성화되는데이는 PKC의활성을매개로하여나타나는것으로알려져있다 30,45). 또한, NF-κB 가 AGE와 RAGE의결합에의하여서도활성화되며, NF-κB 자체가 RAGE의발현도증가시키기때문에 NF-κB 가 AGE에의한병태생리에중심적역할을하는것으로생각된다 46). NF-κB 는초기당뇨때부터활성화되며, RAS 에의하여억제되는것으로보고되고있어대사성요인뿐만아니라혈역학적요인에의한당뇨병성신증의진행에있어 PKC와더불어중심적인역할을할것으로사료된다 47). Cytokines 1. Transforming growth factor-β (TGF-β) 고혈당은사구체내 TGF-β의발현을증가시키는것으로알려져있다 48). TGF-β 는당뇨병성신증에서관찰되는세포외기질축적에관여하는가장중요한 cytokine으로, AGE, ROS, DAG, PKC 그리고 hexosamine 등의자극에의해서도발현이증가된다 49). TGF-β 는세포막의 type II 수용체와결합한후 type I serine/threonine kinase 수용체의인산화를통하여전사인자역할을하는 Smad 2, Smad 3, Co-Smad 4의 complex 형성을일으키며, 이러한과정을통하여 collagen αi, PAI-1, Jun B 그리고 fibronectin 등의전사를조절한다 50). Smad 이외에도당뇨병성신증에서 ERK, p38 MAPK 를포함하는 MAPK 도 TGF-β signaling 과관련이있는신호전달경로로알려져있다 51,52). 당뇨병환자의사구체및소변에서 TGF-β의발현및배설증가 53) 와당뇨백서에서 TGF-β에대한 neutralizing antibody 의투여로인한당뇨병성신증의병리소견의호전은당뇨병성신증에서 TGF-β가관여함을시사하는소견이다 54). 2. Vascular endothelial growth factor 당뇨병성신증에서신장조직및소변내 VEGF 가증가되어있음이보고되었으며 55), 이러한 VEGF의증가와 PKC 활성화사이의연관성이밝혀짐으로써 VEGF가당뇨병성신증의진행과관련이있는한요소로여겨지고있다 56). VEGF의발현은고포도당, TGF-β 그리고 angiotensin II 의해서도영향을받는데, VEGF는 endothelial nitric oxide의생성을증가시켜초기당뇨병성신증에서의과여과와 vasodilatation에관여하는것으로보고되고있다 55). 또한, VEGF 를억제할경우당뇨병성신증동물에서단백뇨가감소되었 으며 57), VEGF에대한 neutralizing antibody를투여한제2형당뇨생쥐에서사구체비후와메산지움내기질축적이억제되었다는연구결과들은당뇨병성신증의발생및진행에있어서 VEGF의역할을뒷받침해주고있다 58). 반면, 족세포에서발현되는 VEGF가사구체혈관내피세포 (endothelial cell) 의생존에필수적일뿐만아니라메산지움세포의형성과분화에중요한역할도하는것으로알려져있다. 그럼에도불구하고, 당뇨병성신증과 VEGF 사이의상세한연관성에대해서는향후더많은연구가필요할것으로생각된다 59). 3. Inflammatory cytokine Interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α 그리고 MCP-1 등의염증성 cytokine도당뇨병성신증의진행에관여하는것으로보고되고있다. 1991년 Hasegawa 등 60) 이당뇨백서의사구체기저막을복막대식세포 (peritoneal macrophage) 와같이배양한경우비당뇨사구체기저막에비하여 TNF-α와 IL-1의분비가증가되었음을보고하여당뇨병성신증의진행에염증성 cytokine이관여할수있음을시사하였다. 염증성 cytokine은염증반응을나타내는효과이외에도신장조직에직접적인영향을미치기도하는데, IL-6는메산지움세포에직접작용하여세포사멸및세포외기질의생성증가를유도하는것으로알려져있으며 61), MCP-1 의경우고포도당으로자극한메산지움세포에서 CCR2와의결합을통하여직접적으로 fibronectin과 collagen IV의생성이증가되었다는보고도있다 62). 또한, IL-1과 TNF-α은메산지움세포에서 prostaglandin 생성에관여하여사구체내의혈역학적변화를야기시키는것으로보고되고있다 60). 결론당뇨병성신증은혈역학적요인과당뇨와관련된대사성요인에의하여발생하며, 여기에는각종세포내신호전달경로와여러 cytokine이작용을한다. 이러한기전을바탕으로당뇨병성신증의발생및진행을억제시키기위한수많은치료방법이연구되고있는데, RAS 차단에대한연구는환자및동물을대상으로광범위하게진행되어왔으며, 현재까지당뇨병성신증의가장중요한치료수단으로정립되어있다. 이외에도 AGE를억제하는약제나 PKC 등의세포내신호전달경로를차단하는약제가당뇨병성신증의새로운치료방법으로시도되고있다

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract