Ma J, Weisberg A, Griffin J P, Vaughan D E, Fogo A B, Brown N J
Division of Pediatric Nephrology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602, USA.
Kidney Int. 2006 Mar;69(6):1064-72. doi: 10.1038/sj.ki.5000201.
This study tests the hypothesis that plasminogen activator inhibitor-1 (PAI-1) contributes to aldosterone-induced renal and cardiac injury. The effects of 12-week aldosterone (2.8 microg/day)/salt (1% drinking water) versus vehicle/salt on renal and cardiac histology and mRNA expression were determined in wild-type (WT) and PAI-1 deficient (PAI-1(-/-)) mice. Systolic blood pressure was similar in aldosterone-infused WT and PAI-1(-/-) mice until 12 weeks, when it was significantly higher in the WT mice. At 12 weeks, urine volume, sodium excretion, and sodium/potassium ratio were similarly increased in the two aldosterone-infused groups. In contrast, urine albumin excretion was greater in aldosterone-infused WT mice (mean+/-s.d.: 699.0+/-873.0 microg/24 h) compared to vehicle-infused WT (23.6+/-9.0 microg/24 h, P=0.003) or aldosterone-infused PAI-1(-/-) mice (131.6+/-110.6 microg/24 h, P=0.007). Aldosterone increased glomerular area to a greater extent in WT (4651+/-577 versus 3278+/-488 microm2/glomerulus in vehicle-infused WT, P<0.001) than in PAI-1(-/-) mice (3713+/-705 microm2/glomerulus, P=0.001 versus aldosterone-infused WT), with corresponding mesangial expansion. Renal collagen content was also increased in aldosterone-infused WT versus PAI-1(-/-) mice. In WT mice, aldosterone increased renal mRNA expression of PAI-1, collagen I, collagen III, osteopontin, fibronectin, monocyte chemoattractant protein-1 (MCP-1), and F4/80 (all P<0.05), but not transforming growth factor beta (TGF-beta). In PAI-1(-/-) mice, aldosterone increased renal expression of collagen I, osteopontin, fibronectin, and MCP-1, and tended to increase collagen III. Renal osteopontin expression was diminished in aldosterone-treated PAI-1(-/-) compared to aldosterone-treated WT mice (P=0.05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1(-/-) mice. PAI-1 contributes to aldosterone-induced glomerular injury.
本研究检验纤溶酶原激活物抑制剂-1（PAI-1）导致醛固酮诱导的肾和心脏损伤这一假说。在野生型（WT）和PAI-1基因缺陷（PAI-1(-/-)）小鼠中，测定12周醛固酮（2.8微克/天）/盐（1%饮用水）与赋形剂/盐对肾和心脏组织学及mRNA表达的影响。在醛固酮输注的WT和PAI-1(-/-)小鼠中，收缩压在12周前相似，12周时WT小鼠收缩压显著更高。12周时，两个醛固酮输注组的尿量、钠排泄及钠/钾比值均类似增加。相比之下，醛固酮输注的WT小鼠尿白蛋白排泄量（均值±标准差：699.0±873.0微克/24小时）高于赋形剂输注的WT小鼠（23.6±9.0微克/24小时，P=0.003）或醛固酮输注的PAI-1(-/-)小鼠（131.6±110.6微克/24小时，P=0.007）。醛固酮使WT小鼠肾小球面积增加程度大于PAI-1(-/-)小鼠（醛固酮输注的WT小鼠为4651±577对赋形剂输注的WT小鼠为3278±488平方微米/肾小球，P<0.001），PAI-1(-/-)小鼠为3713±705平方微米/肾小球，与醛固酮输注的WT小鼠相比P=0.001），伴有相应的系膜扩张。醛固酮输注的WT小鼠肾胶原含量也高于PAI-1(-/-)小鼠。在WT小鼠中，醛固酮增加PAI-1、I型胶原、III型胶原、骨桥蛋白、纤连蛋白、单核细胞趋化蛋白-1（MCP-1）及F4/80的肾mRNA表达（均P<0.05），但不增加转化生长因子β（TGF-β）的表达。在PAI-1(-/-)小鼠中，醛固酮增加I型胶原、骨桥蛋白、纤连蛋白及MCP-1的肾表达，并倾向于增加III型胶原的表达。与醛固酮处理的WT小鼠相比，醛固酮处理的PAI-1(-/-)小鼠肾骨桥蛋白表达减少（P=0.05）。醛固酮在WT和PAI-1(-/-)小鼠中诱导心脏肥大但不诱导纤维化。PAI-1导致醛固酮诱导的肾小球损伤。
