Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter

Author:

Sekiguchi Sahoko1,Suzuki Atsushi1,Asano Shogo1,Nishiwaki-Yasuda Keiko1,Shibata Megumi1,Nagao Shizuko2,Yamamoto Naoki3,Matsuyama Mutsushi4,Sato Yutaka5,Yan Kunimasa6,Yaoita Eishin7,Itoh Mitsuyasu1

Affiliation:

1. Division of Endocrinology and Metabolism, Department of Internal Medicine,

2. Education and Research Center of Animal Models for Human Diseases,

3. Laboratory of Molecularbiology and Histochemistry, Joint Research Laboratory, and

4. Department of Surgical Pathology, Fujita Health University, Aichi;

5. Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya;

6. Department of Pediatrics, Kyorin University School of Medicine, Tokyo; and

7. Department of Structural Pathology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Abstract

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.

Publisher

American Physiological Society

Subject

Physiology

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