레닌 억제제가 실험적 사구체 콩팥염에 미치는 효과 - 예비 보고 = Effect of renin inhibition on an experimental glomerulonephritis - a preliminary report

다국어 초록 (Multilingual Abstract)

Purpose : We performed this study in order to investigate the effect of direct renin inhibition on an experimental animal model with nephrotoxic serum nephritis and tried to give useful information for clinical research and renin inhibitor treatment.
Methods : Thirty BALB/c 6-week-old male mice were divided into 4 groups: control group (CO, n=5), control-treatment group with aliskiren (CT, n=5), disease group (DO, n=10), and disease treatment group with aliskiren (DT, n=10). Nephritis was induced by an intravenous injection of 0.25 mg/g weight of rabbit anti-GBM immunoglobulin G. Model 2002 Alzet mini-osmotic pumps (Durect Corp.) for aliskiren infusion were implanted into CT and DT. Each group strain was sacrificed serially one at a time on day 14. We estimated the protein-creatinine ratio in 12-hour-collected urine (UP/Cr) and measured the mesangial matrix score in the PAS-stained kidney of each strain.
Results : One strain at CT and DT died on day 6 and 7, respectively. Each group strain was sacrificed serially at a time on day 10 because DO were seriously ill. The UP/Cr of each group is as follows: CO, 31.24±6.54 mg/mg, CT, 23.38±13.60 mg/ mg, DO, 112.72±10.97 mg/mg, DT 114.07±32.30 mg/mg. There was no significant difference between DO and DT. The mesangial matrix score of each group was CO, 0.23±0.10; CT, 0.13±0.03; DO, 1.90±0.48; and DT, 1.28±0.41, respectively, and there was a significant difference between DO and DT in the extent of mesangial matrix expansion (P=0.008).
Conclusion : We found that renin inhibition was able to suppress the mesangial matrix expansion in experimental mice with acute nephritis, although there were no significant differences in UP/Cr.

국문 초록 (Abstract)

목 적 : 급성 사구체 콩팥염 실험동물을 이용하여 레닌 억제제를 일정기간 투여한 후 정상군과의 비교를 통해 그 효과를 평가함으로써 임상연구 및 치료를 위해 유용한 지식을 제공하고자 이 연구를 시행하였다.
방 법 : 총 30마리의 재태연령 6주, 수컷 BALB/c 생쥐를 정상군(n=5), 정상치료군(n=5), 질병군(n=10), 질병치료군(n=10) 네 집단으로 분류하고 질병은 항사구체 기저막 항체를 주입하여 유발하였다. 질병유발과 동시에 레닌억제제를 osmotic mini pumps를 통해 피하로 투여하였고 질병유발 14일째 쥐를 도살하여 각 군별로 소변의 단백/크레아티닌 비와 각 개체의 사구체의 메산지움의 확장 정도를 점수화하여 비교하였다.
결 과 : 질병 유발 6일째 질병군에서 한 마리, 7일째 질병치료군중 한 마리가 사망하였다. 10일째 질병군 개체들에서 급성 병색이 나타나 각 군별로 질병 유발 10일째 소변의 단백/크레아티닌 비를 산출하였고 도살 후 떼어 낸 콩팥 조직에서 사구체의 메산지움의 확장 정도를 평가하였다. 소변의 단백/크레아티닌 비가 같은 군에 속한 다른 개체들과의 값보다 현저한 차이를 보인 질병군 한 개체를 제외한 후 측정한 결과 정상군은 31.24±6.54 mg/mg, 정상치료군은 23.38±13.60 mg/mg, 질병군은 112.72±10.97 mg/mg, 질병치료군은 114.07±32.30 mg/mg으로 질병군에서 의미 있는 소변 단백/크레아티닌 비의 상승을 확인할 수 있었고(P<0.05) 서로 다른 군들 사이에서는 차이를 나타내지 않았다. 메산지움의 확장 정도는 정상군은 0.23±0.10, 정상치료군은 0.13±0.03, 질병군은 1.90±0.48, 질병치료군은 1.28±0.41로 정상군과 질병군 사이에 유의한 차이가 있는 것으로 나타났고(P< 0.05), 질병군과 질병치료군 사이에서도 P=0.008로 유의한 차이를 나타내었다.
결 론 : 급성 사구체 콩팥염 실험동물을 이용한 레닌 억제의 효과를 알아 본 이번 실험에서 소변의 단백/크레아티닌 비에서 차이는 뚜렷하지 않았지만 메산지움의 확장 정도를 평가한 병리학적 소견에 있어서는 의미 있는 차이를 확인 할 수 있었다.

참고문헌 (Reference)

1 유태현, "고포도당이 족세포내 국소 레닌-안지오텐신계 (Renin-Angiotensin system)에 미치는 영향" 대한신장학회 25 (25): 903-912, 2006

2 Dzau VJ, "Theodore Cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis" 37 : 1047-1052, 2001

3 Nguyen G, "The renin receptor: the facts, the promise and the hope" 12 : 51-55, 2003

4 Rahuel J, "Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin" 7 : 493-504, 2000

5 Hong L, "Renin inhibition reduces hypercholesterolemia- induced atherosclerosis in mice" 118 : 984-993, 2008

6 Huang Y, "Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms" 69 : 105-113, 2006

7 Fisher ND, "Renal vascular responses to renin inhibition with zankiren in men" 57 : 342-348, 1995

8 Ibrahim MM, "RAS inhibition in hypertension" 20 : 101-108, 2006

9 Stanton A, "Potential of renin inhibition in cardiovascular disease" 4 : 6-10, 2003

10 Carey RM, "Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation" 24 : 261-271, 2003

11 Kunz R, "Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease" 148 : 30-48, 2008

12 Kim JH, "Gene expression profiling of anti-GBM glomerulonephritis model: The role of NF-κB in immune complex kidney disease" 66 : 1826-1837, 2004

13 Salant DJ, "Experimental glomerulonephritis" 162 : 421-461, 1988

14 Michel A, "Direct renin inhibition:clinical pharmacology" 86 : 647-654, 2008

15 Karlberg BE, "Cough and inhibition of the renin-angiotensin system" 11 : S49-S52, 1993

16 Kagami S, "Coordinated expression of beta 1 integrins and transforming growth factor-β induced matrix proteins in glomerulonephritis" 69 : 68-76, 1993

17 Zhao Y, "Contribution of bradykinin and nitric oxide to AT2 receptor-mediated differentiation in PC12 W cells" 85 : 759-767, 2003

18 Azizi M, "Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists" 109 : 2492-2499, 2004

19 Rongen GA, "Clinical pharmacokinetics and efficacy of renin inhibitors" 29 : 6-14, 1995

20 Ferrario CM, "Angiotensin-converting enzyme 2 and angiotensin (1-7): an evolving story in cardiovascular regulation" 47 : 515-521, 2006

21 Hernandez R, "Angiotensin II receptor antagonists role in arterial hypertension" 16 (16): S93-S99, 2002

22 Mezzano SA, "Angiotensin II and renal fibrosis" 38 : 635-638, 2001

23 Gradman AH, "Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients" 111 : 1012-1018, 2005

24 Azizi M, "Acute angiotensin converting enzyme inhibition increases the plasma level of the natural stem-cell regulator N-Acetyl-Seryl-Aspartyl-Lysyl-Proline" 97 : 839-844, 1996

25 Yayama K, "Activation of the renin-angiotensin system in anti-glomerular basement membrane antibody-induced glomerulonephritis" 18 : 411-415, 1995

26 Todd PA, "A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure" 31 : 198-248, 1986