생쥐에서 사구체내 Cyclooxygenase-2 과발현이 Puromycin에 의한 발세포 손상에 미치는 영향 = Effect of Glomerular Cyclooxygenase-2 Overexpression on Podocyte Injury Induced by Puromycin in Mice생쥐에서 사구체내 Cyclooxygenase-2 과발현이 Puromycin에 의한 발세포 손상에 미치는 영향

국문 초록 (Abstract)

목적: Cyclooxygenase-2 (COX-2) 억제제 치료가 단백뇨를 감소시키는 것으로 알려진 이후 COX-2가 발세포(podocyte) 손상에 관여할 가능성이 제기되었지만, COX-2가 발세포 손상에 어떤 역할을 하는지는 명확하지 않다. 한편, 생쥐는 발세포에 독성을 가진 puromycin (PAN)을 투여해도 발세포 손상과 단백뇨가 잘 유발되지 않는다. 저자는 COX-2가 발세포 손상에 관여한다면 사구체에 COX-2를 과발현시킨 생쥐는 PAN에 의해 단백뇨가 발생할 것이라고 가정하고, COX-2 유전자 도입 생쥐에 PAN 및 선택적 COX-2 억제제를 투여하여 COX-2가 발세포 손상에 어떤 영향을 미치는지를 알아보고자 하였다. 방법: Wild-type 생쥐 (B6/D2 strain)와 COX-2 유전자 도입 생쥐에 PAN을 투여하였고, 다른 한 군에는 PAN과 함께 선택적 COX-2 억제제 (SC58236)를 투여하였다. PAN은 실험 1일 (15 mg/100 g BW) 및 3일 (30 mg/100 g BW)의 시작 시점에 정맥 주사하였고, SC58236은 PAN을 주사한 직후부터 식용수에 용해시켜 실험기간 내내 경구 투여하였다. 생쥐는 실험 3일 및 10일 종료 시점에 희생시켰으며, 알부민뇨, 족돌기 소실 그리고 사구체내 COX-2와 nephrin의 발현 정도를 조사하였다. 결과: COX-2 유전자 도입 생쥐만 PAN을 투여한 후에 알부민뇨가 발생하였고, 알부민뇨는 선택적 COX-2 억제에 의해 유의하게 억제되었다. 알부민뇨는 3일째에 유의하게 증가하였고 이후에는 정상수준으로 점차 감소하였다. PAN 투여로 알부민뇨가 발생한 COX-2 유전자 도입 생쥐에서 사구 체내 COX-2 발현은 증가하였고 nephrin은 발현이 감소하는 양상을 보였으며, 이러한 변화는 COX-2 억제제 투여로 완화되었다. 이와는 달리, wild-type 생쥐는 PAN 투여 후에도 유의한 변화를 보이지 않았다. 결론: PAN에 반응을 보이지 않는 wild-type 생쥐와는 달리, COX-2 유전자 도입 생쥐는 PAN에 의해 알부민뇨, 발세포 손상 및 COX-2 발현 증가가 나타났고, 이는 선택적 COX-2 억제제에 의해 완화되었다. 이러한 결과는 COX-2가 생쥐에서 PAN에 의한 발세포 손상의 유발인자로 작용하며, COX-2 억제제가 발세포 손상을 완화시킬 수 있음을 시사한다.

다국어 초록 (Multilingual Abstract)

Purpose: The aim of this study is to investigate the effect of glomerular cyclooxygenase-2 (COX-2) overexpression on podocyte injury by puromycin aminonucleoside (PAN) in nephrin-driven COX-2 transgenic mice. Methods: We administrated PAN intravenously on day-1 (15 mg/100 g body weight) and day-3 (30 mg/100 g body weight) in wild type (male B6/D2 mice) and COX-2 transgenic mice. An additional group received a selective COX-2 inhibitor (SC58236) with PAN. The animals from each group were sacrificed at the end of day-3 and 10. We investigated albuminuria, foot process effacement and glomerular COX-2 and nephrin expression. Results: PAN induced albuminuria only in COX-2 transgenic mice, with the peak on day-3. Selective COX-2 inhibition significantly reduced albuminuria. EM examination demonstrated foot process effacement, which was improved partially by selective COX-2 inhibition, in COX-2 transgenic mice treated with PAN on day-3. Glomerular COX-2 expression increased significantly on day-3 in COX-2 transgenic mice treated with PAN, whereas expression of nephrin showed a tendency to decrease on day-3. These changes of expression of COX-2 and nephrin were partly attenuated by selective COX- 2 inhibition. Unlike COX-2 transgenic mice, wild-type mice did not show any changes even after PAN treatment. Conclusion: In COX-2 transgenic mice, PAN induced albuminuria, podocyte injury and up-regulation of glomerular COX-2, which were ameliorated by selective COX-2 inhibitor. These results suggest that COX-2 may play an important role in increasing susceptibility of podocytes to injury and selective COX-2 inhibition may ameliorate podocyte injury.

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