Integrated Laboratory of Traditional Chinese Medicine and Western Medicine, Peking University First Hospital, Beijing, 100034, People's Republic of China.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Arch Pharm Res. 2018 Aug;41(8):838-847. doi: 10.1007/s12272-018-1061-z. Epub 2018 Aug 13.
Recently, aberrantly high levels of D-ribose have been discovered in type II diabetic patients. D-ribose glycates proteins more rapidly than D-glucose, resulting in the production of advanced glycation end products (AGEs). Accumulations of these products can be found in impaired renal function, but the mechanisms are poorly understood. The present study tested whether D-ribose induces renal dysfunction via the RAGE-dependent NF-κB signaling pathway. In vivo, administration of D-ribose was found to lower blood glucose and regulate insulin tolerance. Compared to controls, urine nitrogen and creatinine excretion were increased in mice receiving D-ribose and were accompanied by severe pathological renal damage. Furthermore, immunohistochemistry showed that NF-κB, AGEs, and receptor of AGEs (RAGE) increased in the kidneys of the mice with D-ribose treatment. In vitro, by western blot and immunofluorescent staining, we confirmed that D-ribose induced NF-κB activation and accumulation of AGEs and RAGE in mesangial cells. By co-immunoprecipitation, we found that the pull-down of RAGE remarkably increased the expression of NF-κB. Silencing the RAGE gene blocked the phosphorylation of NF-κB induced by D-ribose. These results strongly suggest that D-ribose induced NF-κB inflammation in a RAGE-dependent manner, which may be a triggering mechanism leading to nephropathy.
最近，研究人员在 II 型糖尿病患者中发现了异常高水平的 D-核糖。D-核糖比 D-葡萄糖更容易糖化蛋白质，从而产生晚期糖基化终产物（AGEs）。这些产物的积累可在肾功能受损时发现，但机制尚不清楚。本研究通过 RAGE 依赖性 NF-κB 信号通路检测 D-核糖是否通过诱导肾损伤。在体内，D-核糖的给药被发现可降低血糖并调节胰岛素耐受性。与对照组相比，给予 D-核糖的小鼠的尿氮和肌酐排泄增加，并且伴有严重的肾脏病理损伤。此外，免疫组织化学显示 D-核糖处理的小鼠肾脏中 NF-κB、AGEs 和 AGEs 受体（RAGE）增加。在体外，通过 Western blot 和免疫荧光染色，我们证实 D-核糖诱导 NF-κB 激活以及肾小球系膜细胞中 AGEs 和 RAGE 的积累。通过免疫共沉淀，我们发现 RAGE 的下拉显著增加了 NF-κB 的表达。沉默 RAGE 基因可阻断 D-核糖诱导的 NF-κB 磷酸化。这些结果强烈表明，D-核糖以 RAGE 依赖性方式诱导 NF-κB 炎症，这可能是导致肾病的触发机制。
