title: Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter.
abstract: Uptake of P(i) at 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 P(i) transporter Pit-1 to explore the role of extracellular P(i) in 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 P(i) uptake in podocytes than wild-type rats, especially under low P(i) concentration. 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.
authors.affiliation: Div. of Endocrinology and Metabolism, Dept. of Internal Medicine, Fujita Health Univ., Kutsukake, Toyoake, Aichi 470-1192, Japan. aslapin@fujita-hu.ac.jp
authors.forename: Sahoko
authors.initials: S
authors.lastname: Sekiguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Shogo
authors.initials: S
authors.lastname: Asano
authors.forename: Keiko
authors.initials: K
authors.lastname: Nishiwaki-Yasuda
authors.forename: Megumi
authors.initials: M
authors.lastname: Shibata
authors.forename: Shizuko
authors.initials: S
authors.lastname: Nagao
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Mutsushi
authors.initials: M
authors.lastname: Matsuyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sato
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yan
authors.forename: Eishin
authors.initials: E
authors.lastname: Yaoita
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Itoh
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D007150:Immunohistochemistry; D017136:Ion Transport; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D010710:Phosphates / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics / Q000378:metabolism*
chemical_list: D010710:Phosphates; D050611:Sodium-Phosphate Cotransporter Proteins, Type III