Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Sci Rep. 2018 Feb 8;8(1):2686. doi: 10.1038/s41598-018-21176-5.
The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE-RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.
醛固酮受体（MR）及其下游信号通路在高血压肾损伤中发挥重要作用。晚期糖基化终产物（AGE）与其受体（RAGE）的相互作用参与了肾脏疾病的进展。然而，AGE-RAGE 轴与 MR 系统在肾脏功能障碍中的病理串扰尚不清楚。我们在体外筛选了针对 RAGE 的 DNA-适体（RAGE-apt），并研究了其在去氧皮质酮醋酸盐（DOCA）/盐诱导的高血压小鼠单侧肾切除模型中的肾损伤作用。在 DOCA 小鼠的足细胞中，RAGE、GTP 结合的 Rac-1（Rac1）和 MR 共定位。RAGE 基因缺失显著抑制了 DOCA 小鼠的系膜基质扩张和肾小管间质纤维化，这与肾小球氧化应激、MR、Rac1 和尿白蛋白排泄（UAE）水平的降低有关。RAGE-apt 减轻了 DOCA 小鼠肾脏中羧甲基赖氨酸（CML）、RAGE、硝基酪氨酸、Rac1 和 MR 水平的增加，并降低了 UAE。醛固酮（Aldo）增加了鼠足细胞中的硝基酪氨酸、CML 和 RAGE 基因表达，而 CML 刺激了 MR 和 Rac1 水平，这些水平被 RAGE-apt 阻断。本研究表明 AGE-RAGE 轴与 Aldo-MR 系统之间存在串扰，提示 RAGE-apt 可能是治疗与 MR 相关的肾脏疾病的一种新的治疗工具。
