Acta Diabetol. 2013 Dec;50(6):965-9. doi: 10.1007/s00592-013-0492-8.
Diabetic nephropathy (DN) is the major cause of chronic kidney disease in developed countries and contributes significantly to increased morbidity and mortality among diabetic patients. Morphologically, DN is characterized by tubulo-interstitial fibrosis, thickening of the glomerular basement membrane and mesangial expansion mainly due to accumulation of extracellular matrix (ECM). ECM turnover is regulated by metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) activities. In diabetic conditions, TIMP3 expression in kidney is strongly reduced, but the causes of this reduction are still unknown. The aim of this study was to elucidate at least one of these mechanisms which relies on differential expression of TIMP3-targeting microRNAs (miRs) in a hyperglycemic environment either in vitro (MES13 cell line) or in vivo (mouse kidney and human biopsies). Among the TIMP3-targeting miRs, miR-21 and miR-221 were significantly upregulated in kidneys from diabetic mice compared to control littermates, and in a mesangial cell line grown in high glucose conditions. In human samples, only miR-21 expression was increased in kidney biopsies from diabetic patients compared to healthy controls. The expression of miR-217, which targets TIMP3 indirectly through downregulation of SirT1, was also increased in diabetic kidney and MES13 cell line. In agreement with these result, SirT1 expression was reduced in mouse and human diabetic kidneys as well as in MES13 mesangial cell line. TIMP3 deficiency has recently emerged as a hallmark of DN in mouse and human. In this study, we demonstrated that this reduction is due, at least in part, to increased expression of certain TIMP3-targeting miRs in diabetic kidneys compared to healthy controls. Unveiling the post-transcriptional mechanisms responsible for TIMP3 downregulation in hyperglycemic conditions may orient toward the use of this protein as a possible therapeutic target in DN.
糖尿病肾病（DN）是发达国家慢性肾脏病的主要病因，也是糖尿病患者发病率和死亡率升高的主要原因。从形态学上看，DN 的特征是肾小管-间质纤维化、肾小球基底膜增厚和系膜扩张，主要是由于细胞外基质（ECM）的积累。ECM 的转化受金属蛋白酶和金属蛋白酶组织抑制剂（TIMPs）活性的调节。在糖尿病条件下，肾脏中 TIMP3 的表达强烈减少，但这种减少的原因仍不清楚。本研究的目的是阐明至少一种机制，即在高血糖环境中，通过 TIMP3 靶向 microRNAs（miRs）的差异表达，无论是在体外（MES13 细胞系）还是在体内（小鼠肾脏和人类活检）。在 TIMP3 靶向的 miRs 中，与对照同窝仔相比，糖尿病小鼠肾脏和高糖条件下培养的系膜细胞系中 miR-21 和 miR-221 的表达明显上调。在人类样本中，与健康对照组相比，只有糖尿病患者肾脏活检中的 miR-21 表达增加。通过下调 SirT1 间接靶向 TIMP3 的 miR-217 的表达也在糖尿病肾脏和 MES13 细胞系中增加。与这些结果一致，SirT1 在小鼠和人类糖尿病肾脏以及 MES13 系膜细胞系中的表达减少。TIMP3 缺乏最近被认为是糖尿病肾病的一个标志。在这项研究中，我们证明这种减少至少部分是由于与健康对照组相比，糖尿病肾脏中某些 TIMP3 靶向 miRs 的表达增加。揭示高血糖条件下 TIMP3 下调的转录后机制可能会将这种蛋白作为糖尿病肾病的潜在治疗靶点。
