The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes
The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes
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DOI：
10.1681/asn.2017060627
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发表时间：
2018-04-01
影响因子：
13.6
通讯作者：
Park, Cheol Whee
中科院分区：
文献类型：
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作者：
Kim, Yaeni;Lim, Ji Hee;Park, Cheol Whee
脂联素通过脂联素受体（AdipoRs）激活腺苷酸活化蛋白激酶（AMPK）/过氧化物酶体增殖激活受体α（PPAR α）通路，对糖尿病肾病（DN）发挥肾脏保护作用。AdipoRon是一种口服活性合成脂联素受体激动剂。我们研究了27例2型糖尿病患者AdipoRs的表达和相关的细胞内途径，并检查了AdipoRonon对雄性C57 BLKS/J db/db小鼠、肾小球内皮细胞（GECs）和足细胞DN发展的影响。肾小球硬化和肾小管间质纤维化的程度与人肾功能恶化相关。在早期糖尿病肾病患者的肾小球中，AdipoR 1、AdipoR 2和Ca 2 +/钙调素依赖性蛋白激酶β（CaMKK β）的表达以及磷酸化肝激酶B1（LKB 1）和AMPK阳性细胞的数量显著减少。AdipoRon治疗恢复了db/db小鼠中糖尿病诱导的肾脏改变。AdipoRon通过直接激活肾内AdipoR 1和AdipoR 2发挥肾脏保护作用，其增加CaMKK β，磷酸化Ser（431）LKB 1，磷酸化Thr（172）AMPK和PPAR α表达，与脂联素的全身作用无关。AdipoRon诱导的糖尿病诱导的氧化应激改善和肾脏细胞凋亡抑制改善了与脂质蓄积和内皮功能障碍相关的相关细胞内途径。在高糖处理的人GEC和鼠足细胞中，AdipoRon增加细胞内Ca 2+水平，激活CaMKK β/磷酸化Ser（431）LKB 1/磷酸化Thr（172）AMPK/PPAR α通路和下游信号传导，从而减少高糖诱导的氧化应激和凋亡，改善内皮功能障碍。AdipoRon通过在肾脏中证明的相同途径进一步产生心脏保护作用。我们的研究结果表明，AdipoRon通过激活细胞内Ca 2 +/LKB 1-AMPK/PPAR α通路改善GEC和足细胞损伤，表明其治疗2型糖尿病相关DN的疗效。
Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-alpha (PPAR alpha) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type2 diabetes and examined the effects of AdipoRonon DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase-beta (CaMKK beta) and numbers of phosphorylated liver kinaseB1(LKB1)-and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKK beta, phosphorylated Ser(431)LKB1, phosphorylated Thr(172)AMPK, and PPAR alpha expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKK beta/phosphorylated Ser(431)LKB1/phosphorylated Thr(172)AMPK/PPAR alpha pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPAR alpha pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.