Arai Hidenori, Nagai Kojiro, Doi Toshio
Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Vitam Horm. 2008;78:375-92. doi: 10.1016/S0083-6729(07)00015-5.
Nephropathy is one of the most common and severe complications of diabetes mellitus. The mechanism of diabetic nephropathy, however, remains incompletely understood. To elucidate the mechanism of diabetic nephropathy, we focus on the role of a vitamin K-dependent growth factor, growth arrest-specific gene 6 (Gas6), and its receptor Axl in the pathogenesis of diabetic nephropathy. We used streptozotocin (STZ)-induced diabetic rats and mice as a model of diabetic nephropathy and examined the role of Gas6 and Axl in the development of diabetic nephropathy. We also studied signaling mechanisms involved in mesangial hypertrophy characteristic of the early phase of diabetic nephropathy in vitro. After 12 weeks of STZ injection, the glomerular expression of Gas6 and Axl was increased along with the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. Administration of warfarin, which inactivates Gas6, inhibited mesangial and glomerular hypertrophy and the increase in albuminuria in STZ-rats. Warfarin treatment also inhibited the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. To demonstrate the specific role of Gas6, we showed that these findings were recapitulated in STZ-induced Gas6-knockout mice and confirmed the role of Gas6 in the development of diabetic nephropathy in vivo. In vitro stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Thus, we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy, where the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.
肾病是糖尿病最常见且最严重的并发症之一。然而，糖尿病肾病的发病机制仍未完全明确。为阐明糖尿病肾病的发病机制，我们重点研究了维生素K依赖性生长因子生长停滞特异性基因6（Gas6）及其受体Axl在糖尿病肾病发病过程中的作用。我们使用链脲佐菌素（STZ）诱导的糖尿病大鼠和小鼠作为糖尿病肾病模型，研究Gas6和Axl在糖尿病肾病发展中的作用。我们还在体外研究了糖尿病肾病早期特征性的系膜细胞肥大所涉及的信号传导机制。注射STZ 12周后，Gas6和Axl的肾小球表达增加，同时Akt、p70 S6激酶和4E-BP-1的磷酸化水平也升高。给予可使Gas6失活的华法林，可抑制STZ诱导的大鼠系膜和肾小球肥大以及蛋白尿增加。华法林治疗还可抑制Akt、p70 S6激酶和4E-BP-1的磷酸化。为证明Gas6的特定作用，我们发现这些结果在STZ诱导的Gas6基因敲除小鼠中得到重现，并在体内证实了Gas6在糖尿病肾病发展中的作用。体外使用Gas6刺激系膜细胞可导致系膜细胞肥大。与5.6 mmol/l葡萄糖刺激相比，25 mmol/l葡萄糖刺激细胞可增加Gas6/Axl的表达和系膜细胞大小。LY294002和雷帕霉素可阻断Gas6诱导的Akt/mTOR信号通路激活和系膜细胞肥大。因此，我们发现了糖尿病肾病发展过程中通过Gas6/Axl介导的途径导致肾小球肥大的新机制，其中Akt/mTOR信号通路是Gas6介导的系膜和肾小球肥大的关键信号级联反应。抑制糖尿病患者的Gas6/Axl信号通路可能有助于减缓糖尿病肾病的进展。
