Huang Y, Lin S, Zhou J
Department of Nephrology, Huashan Hospital, Shanghai Medical University, Shanghai 200040, China.
Chin Med J (Engl). 1998 Aug;111(8):698-704.
To explore the relationship between receptor for advanced glycosylation end products (RAGE) gene expression in the kidneys of diabetic rats and the role of aminoguanidine on it.
Among four groups of rats, 2 groups received streptozotocin (STZ) to induce diabetics (DM) and were followed by either aminoguanidine (AG) treatment for 12 weeks or no therapy. Two groups of normal rats in which one received AG and the other given water served as control (Con). Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the amount of receptor of advanced glycosylation and products (RAGE) messenger RNA (mRNA) expression.
After 4 weeks of diabetes inducement, RAGE mRNA levels showed a continuous increase up to 12 weeks both in diabetic renal cortex and medulla compared with mRNA levels at the end of 2 weeks. The RAGE mRNA levels in renal cortex and medulla of control rats did not change significantly with age. AG as the prototype inhibitor of advanced glycosylation end products (AGEs) formation, when administered to diabetic rats for 4 weeks, had no visible effect on the alterations of renal RAGE mRNA in diabetes. By continuous administration up to 8 weeks, those alterations of RAGE mRNA both in diabetic renal cortex and medulla were all ameliorated [P < 0.05, (diabetes without AG) versus (diabetes with AG)]. In addition, diabetic animals had a progressive increase in urinary protein excretion compared to control rats from week 4 onwards. Similarly, after 8 weeks diabetic rats had significantly higher glycated Hb (GHb) (DM without AG vs Con: 7.71 +/- 0.22% vs 2.95 +/- 0.52% P < 0.001). AG treatment for 8 weeks decreased GHb by 24.78% and retarded the rate of rise in albuminuria in diabetic rats as compared with that in untreated diabetic rats (DM with AG vs DM without AG: 22.04 +/- 0.91 micrograms/24 h vs 70.25 +/- 13.05 micrograms/24 h, P < 0.001).
Gene expression of RAGE in renal cortex and medulla was altered in diabetic rats and excessive gene expression of RAGE in kidney tissue may enhance the interactions between advanced glycosylation end products (AGEs) and its receptor (RAGE) which would contribute to the development of diabetic nephropathy. Cumulative AGEs play an important role in increasing RAGE gene expression in vivo. The decrease of AGEs level by AG therapy ameliorate the abnormal regulation of RAGE gene expression.
探讨糖尿病大鼠肾脏中晚期糖基化终末产物受体（RAGE）基因表达情况以及氨基胍对其的作用。
将四组大鼠中的两组用链脲佐菌素（STZ）诱导糖尿病（DM），随后一组用氨基胍（AG）治疗12周，另一组不治疗。两组正常大鼠，一组给予AG，另一组给予水作为对照（Con）。采用逆转录聚合酶链反应（RT-PCR）检测晚期糖基化终末产物受体（RAGE）信使核糖核酸（mRNA）表达量。
糖尿病诱导4周后，与2周时的mRNA水平相比，糖尿病大鼠肾皮质和髓质中的RAGE mRNA水平持续升高直至12周。对照大鼠肾皮质和髓质中的RAGE mRNA水平不随年龄显著变化。作为晚期糖基化终末产物（AGEs）形成的原型抑制剂，AG给予糖尿病大鼠4周时，对糖尿病时肾脏RAGE mRNA的改变无明显影响。持续给药至8周，糖尿病大鼠肾皮质和髓质中RAGE mRNA的这些改变均得到改善[P<0.05，（未用AG的糖尿病组）与（用AG的糖尿病组）相比]。此外，从第4周起，与对照大鼠相比，糖尿病动物尿蛋白排泄逐渐增加。同样，糖尿病大鼠8周后糖化血红蛋白（GHb）显著升高（未用AG的糖尿病组与对照组：7.71±0.22%对2.95±0.52%，P<0.001）。与未治疗的糖尿病大鼠相比，AG治疗8周使GHb降低24.78%，并延缓了糖尿病大鼠蛋白尿的上升速率（用AG的糖尿病组与未用AG的糖尿病组：22.04±0.91微克/24小时对70.25±13.05微克/24小时，P<0.001）。
糖尿病大鼠肾皮质和髓质中RAGE的基因表达发生改变，肾组织中RAGE基因的过度表达可能增强晚期糖基化终末产物（AGEs）与其受体（RAGE）之间的相互作用，这可能有助于糖尿病肾病的发展。累积的AGEs在体内增加RAGE基因表达中起重要作用。AG治疗降低AGEs水平可改善RAGE基因表达的异常调节。
