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首页> 外文期刊>Journal of the American Society of Nephrology: JASN >Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy
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Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

机译：硫氧还蛋白相互作用蛋白缺乏症可预防糖尿病性肾病

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Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogen-activated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP(-/-), and TxNIP(+/-) mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP(-/-) mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxN I P-/mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-beta 1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (11,113 mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP(-/-) mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O-2(-) generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.
机译：硫氧还蛋白相互作用蛋白（TxNIP）（硫醇氧化还原酶硫氧还蛋白的内源性抑制剂）的表达被高葡萄糖（HG）增强并促进氧化应激。我们以前曾报道过，TxNIP缺陷的系膜细胞显示出免受HG诱导的活性氧，丝裂原活化的蛋白激酶磷酸化和胶原蛋白表达的保护。在这里，我们调查了TxNIP在糖尿病性肾病（DN）体内发病机理中的潜在作用。用低剂量链脲佐菌素使野生型（WT）对照，TxNIP（-/-）和TxNIP（+/-）小鼠具有相同的糖尿病水平。与野生型小鼠相反，糖尿病并未增加TxNIP（-/-）小鼠的蛋白尿，蛋白尿，血清胱抑素C或血清肌酐水平。肾脏的形态计量学研究显示，糖尿病WT小鼠的肾小球基底膜增厚，足细胞消失，而糖尿病TxN I P- /小鼠则没有这些变化。免疫组织化学分析显示，仅在WT糖尿病小鼠中，肾小球TGF-β1，胶原IV和纤维化水平显着增加。另外，仅WT糖尿病小鼠在氧化应激（硝基酪氨酸，尿中的8-羟基-2-脱氧-鸟苷）和炎症（11,113 mRNA，F4 / 80免疫组织化学）上显示出显着增加。 Nox4编码的mRNA和蛋白质的表达水平仅在糖尿病WT动物中增加。在糖尿病WT小鼠中发现了通过Wilms的肿瘤1和nephrin染色以及尿中nephrin浓度评估的足细胞的大量损失，但没有发现TxNIP（-/-）小鼠。此外，在暴露于HG的培养的人类足细胞中，用siRNA敲低TxNIP可消除增加的线粒体O-2（-）生成和凋亡。这些数据表明，TxNIP在DN的进展中具有关键作用，并且可能是有希望的治疗靶标。

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