Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria

Hideaki Shimizu, Shoichi Maruyama, Yukio Yuzawa, Tomomi Kato, Yusuke Miki, Satoshi Suzuki, Waichi Sato, Yoshiki Morita, Hiroki Maruyama, Kensuke Egashira, Seiichi Matsuo

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Abstract

It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for α-smooth muscle actin (αSMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-β1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.

Original languageEnglish
Pages (from-to)1496-1505
Number of pages10
JournalJournal of the American Society of Nephrology
Volume14
Issue number6
DOIs
Publication statusPublished - 01-06-2003

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All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Shimizu, H., Maruyama, S., Yuzawa, Y., Kato, T., Miki, Y., Suzuki, S., Sato, W., Morita, Y., Maruyama, H., Egashira, K., & Matsuo, S. (2003). Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. Journal of the American Society of Nephrology, 14(6), 1496-1505. https://doi.org/10.1097/01.ASN.0000069223.98703.8E