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Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin

Journal of Nephrology Aims and scope Submit manuscript

Abstract

Background

The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain.

Methods

The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed.

Results

mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 ± 97.0 vs. 359.0 ± 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats.

Conclusions

Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state.

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Acknowledgments

This work was supported by Grant-Aids for Scientific Research (B: 23390224 to H. Kawachi, and C: 23591186 to Y. Tomita) and Grant-Aid for Young Sciences (B: 24790839 to Y. Fukusumi) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The authors would like to express their gratitude to Ms. Tomoyo Kobayashi and Ms. Erina Kowada for their technical support.

Conflict of interest

Dr. Kawachi has received grant support from Dainippon Sumitomo Pharma Co. Ltd.; however the research was conceived and executed independently. Irbesartan used in this study was gifted from Dainippon Sumitomo Pharma Co. Ltd.; however the study was executed independently without any participation of the company.

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Correspondence to Hiroshi Kawachi.

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Takahashi, A., Fukusumi, Y., Yamazaki, M. et al. Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin. J Nephrol 27, 627–634 (2014). https://doi.org/10.1007/s40620-014-0147-z

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  • DOI: https://doi.org/10.1007/s40620-014-0147-z

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