Model of robust induction of glomerulosclerosis in mice: Importance of genetic background
Model of robust induction of glomerulosclerosis in mice: Importance of genetic background
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DOI：
10.1046/j.1523-1755.2003.00058.x
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发表时间：
2003-07-01
影响因子：
19.6
通讯作者：
Fogo, AB
中科院分区：
文献类型：
--
作者：
Ma, LJ;Fogo, AB
背景。越来越多的证据表明，遗传背景在进展性肾小球硬化的发展中起重要作用。进行性肾脏疾病的残肾模型（RKM）在大鼠身上得到了广泛的应用。然而，C57BL/6小鼠对极截肢或肾动脉结扎引起的RKM肾小球硬化均有抵抗性。在129/Sv小鼠中应用的极切除方案仅引起轻度肾小球硬化。我们在此提出了一种高度可重复性的改进的RKM方法，成功地建立了小鼠肾小球硬化模型。雄性C57BL/6 （N = 17）、129/Sv （N = 20）和Swiss-Webster （N = 3）小鼠经RKM后，结扎左肾动脉下支产生约三分之一的梗死；烧灼切除左肾上极（约三分之一肾大小），切除右肾，共行5/6肾切除术（Nx）。在一些C57BL/6小鼠中，7/8肾切除术是通过烧灼从左肾上极切除额外的肾块来诱导的。使用尾袖血压监测仪测量清醒小鼠的收缩压（BP），并在肾切除术后9、12、18和24周处死动物。取肾进行形态学分析。5/6肾切除术后，C57BL/6小鼠的血压随着时间的推移略有升高，与基线血压相比无显著差异，除了8周（0,98 +/- 1 mm Hg；第4周，105 +/- 2 mm Hg；第8周，113 4 turn Hg；第12,110 3 mm Hg）。7/8肾切除术后18周，C57BL/6小鼠血压保持正常（1032mmhg）。5/6肾切除术后4 ~ 12周，129/Sv小鼠的血压显著升高（第0周，112 3 mm Hg；第4周，161 9 mm Hg；第8,166 +/- 5 mm Hg；第12,176周5 turn Hg；第4,8和12周与第0周相比P < 0.01）。C57BL / 6小鼠尿蛋白排泄增加仅在5/6肾切除术,4周后,恢复正常在8 - 12周(周0,13.2±1.4毫克/ 24小时,星期4,20.5±1.8毫克/ 24小时,星期8,18.8±1.6毫克/ 24小时,第12周,17.2±1.2毫克/ 24小时,P < 0.05星期4和星期0)129 / Sv老鼠发达显著蛋白尿12周后5/6肾切除术相比,他们的C57BL / 6小鼠基线和水平(0,17.2 + / - 1 mg / 24小时;第4周，14.9 +/- 1.8 mg/24小时；第8周，23.8 +/- 6.7 mg/24小时；第12周，36.3 +/- 6.6 mg/24小时，第12周与第0周比较P < 0.01；P < 0.01 129/Sv vs. C57BL/6)。不同品系肾切除损伤的死亡率不同。10%的C57BL/6和43%的129/Sv在5/6肾切除术后12周内死亡。尽管50%的C57BL/6小鼠在7/8肾切除术后12周死亡，但只有轻度肾小球硬化(
Background. Increasing evidence suggests that genetic background plays an important role in the development of progressive glomerulosclerosis. The remnant kidney model (RKM) of progressive renal disease has been used extensively in rats. However, C57BL/6 mice are resistant to glomerulosclerosis with RKM induced by either pole amputation or renal artery ligation. A pole resection protocol, applied in 129/Sv mice, induced only mild glomerulosclerosis. We present here a highly reproducible, modified RKM approach to successfully establish a glomerulosclerosis model in mice.Methods. Male C57BL/6 (N = 17),129/Sv (N = 20) and Swiss-Webster (N = 3) mice underwent RKM as follows: the lower branch of the left renal artery was ligated to produce about one third infarct; the upper pole of the left kidney (about one third kidney size) was removed by cautery and the right kidney was nephrectomized to induce a total 5/6 nephrectomy (Nx). In some C57BL/6 mice, 7/8 nephrectomy was induced by removing additional renal mass from the upper pole of the left kidney by cautery. Systolic blood pressure (BP) was measured in conscious mice using a tail-cuff blood pressure monitor and animals were sacrificed at 9, 12, 18, and 24 weeks after nephrectomy. Kidneys were harvested for morphologic analysis.Results. BP in C57BL/6 mice increased slightly after 5/6 nephrectomy over time without significant difference compared to baseline blood pressure except at 8 weeks (blood pressure at week 0, 98 +/- 1 mm Hg; week 4, 105 +/- 2 mm Hg; week 8, 113 4 turn Hg; and week 12,110 3 mm Hg). Blood presssure remained normal in C57BL/6 mice at 18 weeks after 7/8 nephrectomy (103 2 mm Hg). Blood pressure in 129/Sv mice increased significantly after 5/6 nephrectomy from 4 to 12 weeks (week 0, 112 3 mm Hg; week 4, 161 9 mm Hg; week 8,166 +/- 5 mm Hg; and week 12,176 5 turn Hg; P < 0.01 weeks 4, 8, and 12 vs. week 0 blood pressure). Urine protein excretion in C57BL/6 mice increased only at 4 weeks after 5/6 nephrectomy, and was back to normal at 8 and 12 weeks (week 0, 13.2 ± 1.4 mg/24 hours; week 4, 20.5 ± 1.8 mg/24 hours; week 8, 18.8 ± 1.6 mg/24 hours; and week 12, 17.2 ± 1.2 mg/24 hours, P < 0.05 week 4 vs. week 0). 129/Sv mice developed significant proteinuria 12 weeks after 5/6 nephrectomy compared to their baseline and to levels achieved in C57BL/6 mice (week 0, 17.2 +/- 1 mg/24 hours; week 4, 14.9 +/- 1.8 mg/24 hours; week 8, 23.8 +/- 6.7 mg/24 hours; and week 12, 36.3 +/- 6.6 mg/24 hours, P < 0.01 week 12 vs. week 0; P < 0.01 129/Sv vs. C57BL/6 at week 12). Mortality varied in response to nephrectomy injury in the different strains. Ten percent of C57BL/6 and 43% of 129/Sv died within 12 weeks after 5/6 nephrectomy. Although 50% of C57BL/6 mice died by 12 weeks after 7/8 nephrectomy, there was only mild glomerulosclerosis (