TY - JOUR
T1 - Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter
AU - Sekiguchi, Sahoko
AU - Suzuki, Atsushi
AU - Asano, Shogo
AU - Nishiwaki-Yasuda, Keiko
AU - Shibata, Megumi
AU - Nagao, Shizuko
AU - Yamamoto, Naoki
AU - Matsuyama, Mutsushi
AU - Sato, Yutaka
AU - Yan, Kunimasa
AU - Yaoita, Eishin
AU - Itoh, Mitsuyasu
PY - 2011/4/1
Y1 - 2011/4/1
N2 - Uptake of Pi 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 Pi transporter Pit-1 to explore the role of extracellular Pi 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 glom-eruli 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 Pi uptake in podocytes than wild-type rats, especially under low Pi 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.
AB - Uptake of Pi 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 Pi transporter Pit-1 to explore the role of extracellular Pi 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 glom-eruli 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 Pi uptake in podocytes than wild-type rats, especially under low Pi 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.
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U2 - 10.1152/ajprenal.00334.2010
DO - 10.1152/ajprenal.00334.2010
M3 - Article
C2 - 21307129
AN - SCOPUS:79954528152
SN - 1931-857X
VL - 300
SP - 848
EP - 856
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 4
ER -