Huang Jau-Shyang, Chuang Lea-Yea, Guh Jinn-Yuh, Yang Yu-Lin, Hsu Min-Shyang
Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan 717, Taiwan, ROC.
Toxicol Appl Pharmacol. 2008 Dec 1;233(2):220-6. doi: 10.1016/j.taap.2008.09.002. Epub 2008 Sep 12.
Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE, or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27(Kip1), collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells.
越来越多的证据表明，晚期糖基化终产物（AGE）在糖尿病肾病（DN）的发展中起主要作用。牛磺酸是一种有充分文献记载的抗氧化剂。为了探讨牛磺酸是否与DN中AGE介导的肾小管间质纤维化改变有关，我们研究了牛磺酸抑制AGE诱导的肾小管上皮细胞肥大的分子机制。我们发现AGE（而非未糖基化的牛血清白蛋白）通过坏死或凋亡导致细胞有丝分裂抑制而非细胞死亡。在这些细胞中，牛血清白蛋白、AGE或抗氧化剂牛磺酸处理后，半胱天冬酶3活性、bcl-2蛋白表达和线粒体细胞色素c释放均无变化。牛磺酸显著阻断了AGE诱导的Raf-1/细胞外信号调节激酶（ERK）激活。此外，牛磺酸、Raf-1激酶抑制剂GW5074和ERK激酶抑制剂PD98059可能具有诱导AGE处理细胞的细胞增殖和细胞周期进程的能力。牛磺酸、GW5074或PD98059抑制AGE诱导的肥大的能力通过以下观察得到证实：它显著降低了细胞大小、细胞肥大指数以及RAGE、p27（Kip1）、IV型胶原和纤连蛋白的蛋白水平。本研究结果表明，牛磺酸可能通过其在AGE诱导的肾小管上皮细胞肥大中使Raf-旦绩测啃爻救诧寻超默1/ERK失活的机制，在DN中发挥潜在的抗纤维化活性。
