Kidneys with heavy proteinuria show fibrosis, inflammation, and oxidative stress, but no tubular phenotypic change
Kidneys with heavy proteinuria show fibrosis, inflammation, and oxidative stress, but no tubular phenotypic change
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DOI：
10.1111/j.1523-1755.2005.00386.x
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发表时间：
2005-07-01
影响因子：
19.6
通讯作者：
Jalanko, H
中科院分区：
文献类型：
--
作者：
Kuusniemi, AM;Lapatto, R;Jalanko, H
背景持续性蛋白尿是导致肾纤维化和终末期肾功能衰竭的主要因素。据信，肾小管上皮细胞通过产生导致纤维化和炎症的介质在该过程中发挥关键作用。芬兰型先天性肾病综合征（NPHS 1）是一种由足细胞蛋白nephrin突变引起的遗传性疾病，导致出生后持续的重度蛋白尿。在这项工作中，我们研究了肾小管间质的变化，发生在NPHS 1肾脏在婴儿期。采用免疫组化、Western blotting和细胞因子抗体阵列技术研究NPHS 1肾切除后的病理变化及促纤维化和促炎症因子的表达。通过测定谷胱甘肽的氧化还原状态来评估肾脏的氧化应激。结果表明：（1）NPHS 1大鼠肾脏在婴儿期发生了严重的肾小管间质病变;（2）通过波形蛋白、α-平滑肌肌动蛋白的表达研究，肾小管上皮细胞未显示向肌成纤维细胞的转化（α-SMA）、胶原和基质金属蛋白酶2和9（3）NPHS 1组织中最丰富的趋化因子为中性粒细胞活化蛋白-2（NAP-2）、巨噬细胞抑制因子（MIF）和单核细胞趋化蛋白-1（MCP-1）;（4）表达CD 14抗原的单核细胞/巨噬细胞是侵袭肾小管的主要炎症细胞;（5）NPHS 1肾动脉和小动脉内膜肥厚，但微血管结构正常;（6）NPHS 1肾过度氧化应激。NPHS 1肾脏中的大量蛋白尿与间质纤维化、炎症和氧化应激相关。然而，肾小管上皮细胞对蛋白尿有抵抗力，并且没有表现出上皮-间质转化。
Background. Sustained proteinuria is a major factor leading to kidney fibrosis and end-stage renal failure. Tubular epithelial cells are believed to play a crucial role in this process by producing mediators leading to fibrosis and inflammation. Congenital nephrotic syndrome of the Finnish type (NPHS1) is a genetic disease caused by mutations in a podocyte protein nephrin, which leads to constant heavy proteinuria from birth. In this work we studied the tubulointerstitial changes that occur in NPHS1 kidneys during infancy.Methods. The pathologic lesions and expression of profibrotic and proinflammatory factors in nephrectomized NPHS1 kidneys were studied by immunohistochemistry, Western blotting, and cytokine antibody array. Oxidative stress in kidneys was assessed by measurement of gluthatione redox state.Results. The results indicated that (1) severe tubulointerstitial lesions developed in NPHS1 kidneys during infancy; (2) tubular epithelial cells did not show transition into myofibroblasts as studied by the expression of vimentin, alpha-smooth muscle actin (alpha-SMA), collagen, and matrix metalloproteinases 2 and 9 (MMP-2 and -9); (3) the most abundant chemokines in NPHS1 tissue were neutrophil activating protein-2 (NAP-2), macrophage inhibiting factor (MIF), and monocyte chemoattractant protein-1 (MCP-1); (4) monocyte/macrophage cells expressing CD14 antigen were the major inflammatory cells invading the interstitium; (5) the arteries and arterioles showed intimal hypertrophy, but the microvasculature in NPHS1 kidneys remained quite normal; and (6) excessive oxidative stress was evident in NPHS1 kidneys.Conclusion. Heavy proteinuria in NPHS1 kidneys was associated with interstitial fibrosis, inflammation, and oxidative stress. The tubular epithelial cells, however, were resistant to proteinuria and did not show epithelial-mesenchymal transition.