The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential
The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential
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DOI：
10.1038/ki.2013.427
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发表时间：
2014-03-01
影响因子：
19.6
通讯作者：
Yamada, Yuichiro
中科院分区：
文献类型：
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作者：
Fujita, Hiroki;Morii, Tsukasa;Yamada, Yuichiro
胰升糖素样肽-1(GLP-1)是一种对多种组织具有抗氧化保护作用的胃肠促胰岛素激素。在这里，我们利用肾病抵抗的C57BL/6-Akita和肾病易感的KK/Ta-Akita小鼠来确定GLP-1是否在糖尿病肾病的发病机制中起作用。通过原位杂交，我们发现GLP-1受体(GLP-1R)在小鼠肾脏的肾小球毛细血管和血管壁表达，而在肾小管不表达。接下来，我们产生了C57BL/6-Akita GLP1R基因敲除小鼠。这些小鼠表现出比野生型C57BL/6-Akita小鼠更高的尿白蛋白水平和更先进的系膜扩张，尽管它们的高血糖水平相当。GLP1R基因敲除C57BL/6-Akita小鼠肾小球超氧化物歧化，肾脏NAD(P)H氧化酶上调，cAMP和蛋白激酶A(PKA)活性降低。GLP-1R激动剂利拉鲁肽可抑制KK/Ta-Akita小鼠肾病的进展，表现为减少蛋白尿和系膜扩张，降低肾小球超氧化物和肾脏NAD(P)H氧化酶水平，并提高肾脏cAMP和PKA活性。这些作用可被腺苷环化酶抑制剂SQ22536和选择性PKA抑制剂H-89取消。因此，GLP-1通过抑制超氧化物的主要来源NAD(P)H氧化酶，以及通过激活cAMP-PKA途径，在慢性高血糖条件下保护肾脏氧化应激增加中起着至关重要的作用。
Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P) H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P) H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P) H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.