MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPARγ pathway in diabetic nephropathy.
MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPARγ pathway in diabetic nephropathy.
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DOI：
10.18632/oncotarget.10283
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发表时间：
2016-07-26
期刊：
影响因子：
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通讯作者：
Bai X
中科院分区：
文献类型：
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作者：
Hou X;Tian J;Geng J;Li X;Tang X;Zhang J;Bai X
已在糖尿病中鉴定了microRNA-27 a（miR-27 a）上调，但miR-27 a在糖尿病肾病（DN）中的肾小管间质纤维化（TIF）中的发病机制尚未阐明。在此，我们发现高糖刺激miR-27 a表达，其直接抑制了NRK-52 E细胞中的PPARγ并促进了纤维化。miR-27 a依赖性PPARγ降低的功能相关性通过miR-27 a在体外和链脲佐菌素诱导的糖尿病大鼠中的抑制或过表达来证明。MiR-27 a通过抑制PPARγ激活TGF-β/Smad 3信号通路，促进结缔组织生长因子（CTGF）、纤连蛋白和I型胶原等纤维化关键介质的表达变化。此外，我们提供的证据表明，血浆miR-27 a上调有助于不利的肾功能和增加TIF在糖尿病大鼠和DN患者的肾组织。值得注意的是，miR-27 a表现出临床和生物学相关性，因为它与血清肌酐升高、蛋白尿、尿N-乙酰基-β-D-氨基葡萄糖苷酶（NAG）和估计肾小球滤过率（eGFR）降低相关。因此，我们提出了miR-27 a-PPAR γ轴在促进DN向更恶化的肾TIF进展中的新作用。监测血浆miR-27 a水平及其与PPARγ的相关性可反映肾TIF的严重程度。靶向miR-27 a可作为DN的潜在治疗方法。
MicroRNA-27a (miR-27a) upregulation has been identified in diabetes, but the pathogenesis of miR-27a in renal tubulointerstitial fibrosis (TIF) in diabetic nephropathy (DN) has not been elucidated. Herein, we found that high glucose stimulated miR-27a expression, which directly inhibited PPARγ and promoted fibrosis in NRK-52E cells. The functional relevance of miR-27a-dependent PPARγ decrease was proven by inhibition or overexpression of miR-27a both in vitro and in streptozotocin-induced diabetic rats. MiR-27a, via repression of PPARγ, activates the TGF-β/Smad3 signaling and contributes to the expressional changes of connective tissue growth factor (CTGF), Fibronectin and Collagen I, key mediators of fibrosis. Furthermore, we provide evidences that plasma miR-27a upregulation contributed to unfavorable renal function and increased TIF in renal tissues of diabetic rats and DN patients. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria, urinary N-acetyl-β-D-glucosaminidase (NAG), and reduced estimated glomerular filtration rate (eGFR). Thus, we propose a novel role of the miR-27a-PPARγ axis in fostering the progression toward more deteriorated renal TIF in DN. Monitoring plasma miR-27a level and its association with PPARγ can be used to reflect the severity of renal TIF. Targeting miR-27a could be evaluated as a potential therapeutic approach for DN.