Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter.
Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter.
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磷酸盐超负荷通过 III 型 Na 依赖性磷酸盐转运蛋白诱导足细胞损伤。
DOI：
10.1152/ajprenal.00334.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Itoh M.
中科院分区：
文献类型：
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作者：
Sekiguchi S;Suzuki A;Asano S;Nishiwaki-Yasuda K;Shibata M;Nagao S;Yamamoto N;Matsuyama M;Sato Y;Yan K;Yaoita E;Itoh M.
在细胞膜上摄取Piat对于维持细胞活力是必不可少的。然而，磷酸盐过载也对细胞造成压力，并可能导致细胞损伤。在本研究中，我们研究了III型Pitransporter Pit-1的转基因过表达的影响，以探讨细胞外Piin在慢性肾病肾小球硬化中的作用。Pit-1转基因（TG）大鼠表现出与低白蛋白血症和血脂异常相关的进行性蛋白尿。透射电子显微镜观察TG大鼠肾脏超微结构，足细胞足突弥漫性消失，肾小球基底膜增厚，自出生后8周开始逐渐加重。TG大鼠在32周龄时死于恶病质。此时，TG大鼠肾小球基底膜增厚，节段性硬化。抗连接蛋白43和抗结蛋白抗体的免疫组化检查提示TG大鼠足细胞的进行性损伤。TG大鼠足细胞的Pi摄取高于野生型大鼠，特别是在低Pi浓度下。当8周龄的野生型和TG大鼠喂食0.6%正常磷酸盐（NP）或1.2%磷酸盐（HP）饮食12周时，HP饮食治疗的TG大鼠表现出更多的进行性蛋白尿和更高的血清肌酐水平比NP饮食治疗的TG大鼠。总之，我们的研究结果表明，Pit-1在大鼠中的过度表达诱导磷酸盐依赖性足细胞损伤和肾小球屏障的损伤，这导致肾小球硬化的进展。
Uptake of Piat the cellular membrane is essential for the maintenance of cell viability. However, phosphate overload is also stressful for cells and can result in cellular damage. In the present study, we investigated the effects of the transgenic overexpression of type III Pitransporter Pit-1 to explore the role of extracellular Piin glomerular sclerosis during chronic renal disease. Pit-1 transgenic (TG) rats showed progressive proteinuria associated with hypoalbuminemia and dyslipidemia. Ultrastructural analysis of TG rat kidney by transmission electron microscopy showed a diffuse effacement of the foot processes of podocytes and a thickening of the glomerular basement membrane, which were progressively exhibited since 8 wk after birth. TG rats died at 32 wk of age due to cachexia. At this time, more thickening of the glomerular basement membrane and segmental sclerosis were observed in glomeruli of the TG rats. Immunohistochemical examination using anti-connexin 43 and anti-desmin antibodies suggested the progressive injury of podocytes in TG rats. TG rats showed higher Piuptake in podocytes than wild-type rats, especially under low Piconcentration. When 8-wk-old wild-type and TG rats were fed a 0.6% normal phosphate (NP) or 1.2% phosphate (HP) diet for 12 wk, HP diet-treated TG rats showed more progressive proteinuria and higher serum creatinine levels than NP diet-treated TG rats. In conclusion, our findings suggest that overexpression of Pit-1 in rats induces phosphate-dependent podocyte injury and damage to the glomerular barrier, which result in the progression of glomerular sclerosis in the kidney.