van den Hoven Mabel J, Waanders Femke, Rops Angelique L, Kramer Andrea B, van Goor Harry, Berden Jo H, Navis Gerjan, van der Vlag Johan
Nijmegen Centre for Molecular Life Sciences, Department of Nephrology, Radboud University Nijmegen Medical Centre, The Netherlands.
Nephrol Dial Transplant. 2009 Sep;24(9):2637-45. doi: 10.1093/ndt/gfp182. Epub 2009 May 9.
Inhibition of the renin-angiotensin-aldosterone system (RAAS) provides renoprotection in adriamycin nephropathy (AN), along with a decrease in overexpression of glomerular heparanase. Angiotensin II (AngII) and reactive oxygen species (ROS) are known to regulate heparanase expression in vivo. However, it is unknown whether this is also the case for aldosterone. Therefore, we further assessed the role of aldosterone, AngII and ROS in the regulation of glomerular heparanase expression.
Six weeks after the induction of AN, rats were treated with vehicle (n = 8), lisinopril (75 mg/L, n = 10), spironolactone (3.3 mg/day, n = 12) or the combination of lisinopril and spironolactone (n = 14) for 12 weeks. Age-matched healthy rats served as controls (n = 6). After 18 weeks, renal heparanase and heparan sulfate (HS) expression were examined by immunofluorescence staining. In addition, the effect of aldosterone, AngII and ROS on heparanase expression in cultured podocytes was determined.
Treatment with lisinopril, spironolactone or their combination significantly blunted the increased glomerular heparanase expression and restored the decreased HS expression in the GBM. Addition of aldosterone to cultured podocytes resulted in a significantly increased heparanase mRNA and protein expression, which could be inhibited by spironolactone. Heparanase mRNA and protein expression in podocytes were also significantly increased after stimulation with AngII or ROS.
Our in vivo and in vitro results show that not only AngII and ROS, but also aldosterone is involved in the regulation of glomerular heparanase expression.
抑制肾素 - 血管紧张素 - 醛固酮系统（RAAS）可在阿霉素肾病（AN）中提供肾脏保护作用，同时降低肾小球乙酰肝素酶的过表达。已知血管紧张素II（AngII）和活性氧（ROS）在体内调节乙酰肝素酶的表达。然而，尚不清楚醛固酮是否也是如此。因此，我们进一步评估了醛固酮、AngII和ROS在调节肾小球乙酰肝素酶表达中的作用。
诱导AN 6周后，大鼠分别接受溶剂（n = 8）、赖诺普利（75 mg/L，n = 10）、螺内酯（3.3 mg/天，n = 12）或赖诺普利与螺内酯联合治疗（n = 14），持续12周。年龄匹配的健康大鼠作为对照（n = 6）。18周后，通过免疫荧光染色检测肾脏乙酰肝素酶和硫酸乙酰肝素（HS）的表达。此外，还测定了醛固酮、AngII和ROS对培养的足细胞中乙酰肝素酶表达的影响。
赖诺普利、螺内酯或它们的联合治疗显著抑制了肾小球乙酰肝素酶表达的增加，并恢复了肾小球基底膜中降低的HS表达。向培养的足细胞中添加醛固酮导致乙酰肝素酶mRNA和蛋白表达显著增加，而螺内酯可抑制这种增加。用AngII或ROS刺激后，足细胞中的乙酰肝素酶mRNA和蛋白表达也显著增加。
我们的体内和体外结果表明，不仅AngII和ROS，而且醛固酮也参与了肾小球乙酰肝素酶表达的调节。
