Watanabe Yusuke, Kobayashi Tatsuya, Yaoita Eishin, Kawachi Hiroshi, Yamauchi Atsushi, Inoue Tsutomu, Shimizu Fujio, Yoshida Yutaka, El-Shemi Adel G A, Okada Hirokazu, Suzuki Hiromichi, Yamamoto Tadashi
Department of Structural Pathology, Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.
Nephrol Dial Transplant. 2004 Apr;19(4):817-22. doi: 10.1093/ndt/gfh026.
How podocytes respond to injury is poorly understood, although podocyte injury in the glomerulus has been proposed as the crucial mechanism in the pathogenesis of proteinuria and focal segmental glomerulosclerosis. An increase in sodium/myo-inositol co-transporter (SMIT) transcripts, an osmoprotective gene, has been demonstrated in a variety of brain injury models. In the present study, we investigated SMIT expression in podocytes in experimental nephrosis.
Two types of nephrosis were induced in rats: puromycin aminonucleoside (PAN) nephrosis and monoclonal antibody (mAb) 5-1-6 nephropathy. Podocyte injury was morphologically distinct in the former type of nephrosis and limited to a minimum in the latter. SMIT expression in isolated glomeruli was estimated by ribonuclease protection assay. Localization of SMIT-expressing cells in glomeruli was examined by in situ hybridization.
SMIT transcripts in glomeruli increased conspicuously in the nephrotic stage of PAN nephrosis, whereas the transcripts in cortices and medullae did not show significant changes. In situ hybridization revealed that podocytes were predominant cells expressing SMIT in the glomerulus. Significant increase of SMIT mRNA in the glomeruli was detected before the onset of massive proteinuria. In contrast, up-regulation of SMIT expression was not observed in mAb 5-1-6 nephropathy, whose urinary protein levels were comparable with those in the nephrotic stage of PAN nephrosis.
These findings suggest that SMIT expression in podocytes is not provoked by an effect of massive proteinuria but by extensive cellular injury.
尽管肾小球足细胞损伤被认为是蛋白尿和局灶节段性肾小球硬化发病机制中的关键机制，但人们对足细胞如何应对损伤了解甚少。在多种脑损伤模型中已证实，一种渗透保护基因——钠/肌醇共转运体（SMIT）的转录本会增加。在本研究中，我们调查了实验性肾病中足细胞的SMIT表达情况。
在大鼠中诱导出两种类型的肾病：嘌呤霉素氨基核苷（PAN）肾病和单克隆抗体（mAb）5-1-6肾病。在前一种肾病类型中，足细胞损伤在形态上较为明显，而在后一种中则限制在最小程度。通过核糖核酸酶保护试验评估分离肾小球中SMIT的表达。通过原位杂交检查肾小球中表达SMIT的细胞的定位。
在PAN肾病的肾病阶段，肾小球中的SMIT转录本显著增加，而皮质和髓质中的转录本未显示出明显变化。原位杂交显示，足细胞是肾小球中表达SMIT的主要细胞。在大量蛋白尿发作之前，就检测到肾小球中SMIT mRNA显著增加。相比之下，在mAb 5-1-6肾病中未观察到SMIT表达上调，其尿蛋白水平与PAN肾病肾病阶段的水平相当。
这些发现表明，足细胞中SMIT的表达不是由大量蛋白尿的作用引起的，而是由广泛的细胞损伤引起的。
