상염색체 우성 다낭신에서 세포자멸사에 대한 연구 = Apoptosis in Autosomal Dominant Polycystic Kidney Disease

다국어 초록 (Multilingual Abstract)

Background:Apoptosis is one of the major histopathologic features of autosomal dominant polycystic kidney disease (ADPKD) and may be causally related to the cystogenesis and the progressive deterioration of the renal function in this population. The purpose of this study is to determine whether transforming growth factor-β1 (TGF-β1)-Smad2/3 signal pathway, antiapoptotic Bcl-2 proteins are involved in apoptotic pathway in the pathogenesis of ADPKD.
Methods:Human polycystic kidneys were collected from four ADPKD patients with end stage renal disease who were taken renal transplantation. We evaluated TdT-mediated dUTP nick end labeling (TUNEL) assay to detect apoptotic DNA fragmentation in polycystic kidneys compared to normal kidneys. Expression of TGF-β1, Smad2/3 and Bcl-2 proteins was also detected by immunohistochemistry.
Results:The number of apoptotic nuclei in polycystic kidneys was markedly increased, as compared with normal kidneys. Apoptotic cells in tubules expressed as a percentage of total tubular cells within 10 random high power fields (×400) were significantly increased in ADPKD group than in normal group (9.01±1.85%, 0.36±0.10%, p=0.020). Apoptotic nuclei were detected not only in cells lining the expanded cystic wall but also in the noncystic tubular epithelial cells. Apoptotic nuclei were also demonstrated in the interstitium occasionally but rarely observed in the glomeruli. Immunohistochemical findings of polycystic kidneys showed increased expression of TGF-β1 proteins and Smad2/3 proteins, and decreased expression of Bcl-2 proteins in cystic and noncystic tubular epitheial cells as opposed to other parts of the kidney, as compared with normal kidneys.
Conclusion:Upregulation of TGF-β1-Smad2/3 signal pathway and decreased anti-apoptotic Bcl-2 protein seem to be involved in apoptotic pathway of ADPKD. (Korean J Nephrol 2005;24(3):366-374)

국문 초록 (Abstract)

목 적:상염색체 우성 다낭신에서 세포자멸사는 주된 조직병리학적 소견의 하나로 이 환자군에서 낭종 형성 및 신기능의 지속적 감소에 관여한다고 여겨지나 그 기전은 명확하지 않다. 이에 저자들은 상염색체 우성 다낭신 환자의 신장 조직에서 세포자멸사 정도와 다양한 기능을 하는 사이토카인으로 세포자멸사에도 관여하는 것으로 알려진 transforming growth factor (TGF)-β1과 그 신호중간물인 Smad2/3, 세포자멸사 억제인자인 Bcl-2 단백질의 발현을 면역조직화학 염색을 통해 알아보고자 하였다.
방 법:말기신부전에 이르러 신이식을 시행하는 상염색체 우성 다낭신 환자 (n=4)의 신장 조직을 얻어 TdT-mediated dUTP nick end labeling (TUNEL) 방법으로 세포자멸사 정도를 판정하고, TGF-β1, Smad2/3, Bcl-2 단백질에 대한 면역조직화학 염색을 시행하여 정상군(n=4)과 비교하였다.
결 과:세뇨관 세포의 세포자멸사는 정상군 (0.36±0.10%)에서는 거의 관찰되지 않았으며, 상염색체 우성 다낭신군 (9.01±1.85%)에서 유의하게 증가되었다 (p=0.020). 상염색체 우성 다낭신군에서의 세포자멸사는 낭종에 배열한 상피세포에서 뿐만 아니라, 비낭종성 세뇨관에서도 관찰되었으며, 일부 간질조직에서도 관찰되었으나, 사구체에서는 거의 관찰되지 않았다. 면역조직화학적 염색으로 상염색체 우성 다낭신군에서는 정상군에서 보다 낭종성 및 비낭종성 세뇨관 상피세포에서 TGF-β1, Smad2/3 단백질의 과발현이 관찰되었으며, Bcl-2 단백질의 발현은 감소되었다.
결 론:상염체 우성 다낭신의 병인이나 진행과정에 세포자멸사가 관여하며, 여기에는 활성화된 TGF-β1-Smad2/3 신호체계와 감소된 Bcl-2가 관여하는 것으로 보인다.

참고문헌 (Reference)

• 1 "Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells" 275 : 39137-39145, 2000
• 2 "The interplay between the Bcl-2 family and death receptor-mediated apoptosis" 1644 : 125-132, 2004
• 3 "The biochemistry of apotosis" 407 : 770-776, 2000
• 4 "TGF-β signaling in renal disease" 13 : 2600-2610, 2002
• 5 "Smad-dependent and Smad-independent pathways in TGF-β family signalling" 425 : 577-584, 2003
• 6 "Sm ad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells" 20 : 879-884, 2001
• 7 "Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia" 271 : 1193-1201, 1996
• 8 "Proliferative activity of cyst epithelium in human renal cystic diseases" 5 : 1462-1468, 1995
• 9 "Polycystic kidney disease in SBM transgenic mice:role of c-myc in disease induction and progression" 152 : 219-229, 1998
• 10 "Polycystic kidney disease" 350 : 151-164, 2004
• 11 "Pathogenesis of autosomal dominant polycystic kidney disease:Role of Apoptosis" 7 : 65-68, 1998
• 12 "New insights into the molecular pathophysiology of polycystic kidney disease" 55 : 1187-1197, 1999
• 13 "Mechanism of apoptosis and its potential role in renal tubular epithelial cell injury" 271 : 477-488, 1996
• 14 "Mechanism of TGF-β-mediated apoptosis" 307 : 1-14, 2002
• 15 "Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor" 118 : 777-784, 1993
• 16 "Expression of bcl-2 and bax in TGF-beta 1-induced apoptosis of L1210 leukemic cells" 75 : 367-374, 1998
• 17 "Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2β" 11 : 1938-1948, 1997
• 18 "Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease(ADPKD)" 13 : 1153-1160, 1996
• 19 "Disruption of epitherial cell-matrix interactions induces apoptosis" 124 : 619-626, 1994
• 20 "Cell-matrix and cell-cell interactions modulate apoptosis of bronchoal epitherial cells" 2772 : 28-37, 1997
• 21 "Caspases,Bcl-2 proteins and apoptosis in autosomal-dominant polycystic kidney disease" 61 : 1220-1230, 2002
• 22 "C-myc as an inducer of polycystic kidney disease in transgenic mice" 39 : 665-671, 1991
• 23 "C-MYC- induced apoptosis in polycystic kidney disease is Bcl-2 and p53 independent" 186 : 1873-1884, 1997
• 24 "Bcl-xL blocks transforming growth factor- beta 1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf- 1-dependent caspase activation in prostate epithelial cells" 276 : 26614-26621, 2001
• 25 "Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair" 75 : 229-240, 1993
• 26 "BCl-2 overexpression prevents apoptosis induced-Madin-Darby canine kideny simple epithelial cyst formation" 55 : 168-178, 1999
• 27 "Apoptotic regulatory proteins in renal injury" 58 : 467-485, 2000
• 28 "Apoptosis in podocytes induced by TGF-beta and Smad7" 108 : 807-816, 2001
• 29 "Apoptosis during an early stage of nephrogenesis induces renal hypoplasia in bcl-2-deficient mice" 148 : 1601-1611, 1996
• 30 "Apoptosis and the kidney" 5 : 12-21, 1994
• 31 "Apoptosis and loss of renal tissue in polycystic kidney diseases" 333 : 18-25, 1995
• 32 "Apopotosis in cystogenesis Hands on or hands off" 55 : 334-335, 1999
• 33 "Abnormal postpartum renal development and cystogenesis in the bcl-2(－/－)mouse" 271 : 184-193, 1996