Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy

Koichiro Kitamoto; Yuichi Machida; Junji Uchida; Yasukatsu Izumi; Masayuki Shiota; Takafumi Nakao; Hiroshi Iwao; Tokihito Yukimura; Tatsuya Nakatani; Katsuyuki Miura

doi:10.1254/jphs.09227FP

Full Papers

Effects of Liposome Clodronate on Renal Leukocyte Populations and Renal Fibrosis in Murine Obstructive Nephropathy

Koichiro Kitamoto, Yuichi Machida, Junji Uchida, Yasukatsu Izumi, Masayuki Shiota, Takafumi Nakao, Hiroshi Iwao, Tokihito Yukimura, Tatsuya Nakatani, Katsuyuki Miura

Author information

Koichiro Kitamoto
Department of Urology, Osaka City University Medical School, Japan
Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Japan
Yuichi Machida
Department of Urology, Osaka City University Medical School, Japan
Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Japan
Junji Uchida
Department of Urology, Osaka City University Medical School, Japan
Yasukatsu Izumi
Department of Pharmacology, Osaka City University Medical School, Japan
Masayuki Shiota
Department of Pharmacology, Osaka City University Medical School, Japan
Takafumi Nakao
Department of Pharmacology, Osaka City University Medical School, Japan
Hiroshi Iwao
Department of Pharmacology, Osaka City University Medical School, Japan
Tokihito Yukimura
Department of Pharmacology, Osaka City University Medical School, Japan
Tatsuya Nakatani
Department of Urology, Osaka City University Medical School, Japan
Katsuyuki Miura
Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Japan

Keywords: obstructive nephropathy, ureteral obstruction, macrophage, dendritic cell, liposome clodronate

JOURNAL FREE ACCESS

2009 Volume 111 Issue 3 Pages 285-292

DOI https://doi.org/10.1254/jphs.09227FP

View "Advance Publication" version (November 6, 2009).

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Abstract

Although liposome-encapsulated clodronate has been used as a means to deplete macrophages from certain tissues, target leukocyte subtypes within the kidney are not clearly known under normal and pathologic conditions. The present study was therefore conducted to examine the effects of liposome clodronate on renal infiltrating cell type following unilateral ureteral obstruction (UUO) and tried to correlate these changes to the mechanisms of early development of renal fibrosis. Renal infiltrating leukocyte subtypes and counts were determined by using multicolor flow cytometric analysis of cell suspensions from obstructed kidneys. UUO for 5 days elicited renal tubular apoptosis and renal fibrosis and showed 4-fold increase in renal leukocytes including monocytes/macrophages, dendritic cells, and T-cells. Repeated administration of liposome clodronate selectively depleted F4/80⁺ monocytes/macrophages and F4/80⁺ dendritic cells but not F4/80⁻ dendritic cells or other cell types in both obstructed and non-obstructed kidneys. Tubular apoptosis and renal fibrosis were also significantly attenuated by liposome clodronate. Increased gene expression of TNF-α and TGF-β observed in obstructed kidneys were markedly attenuated by depletion of renal mononuclear phagocytes. These findings suggest that F4/80⁺ monocytes/macrophages and/or F4/80⁺ dendritic cells play a pivotal role in the development of obstruction-induced tubular apoptosis and renal fibrosis, possibly through TNF-α and TGF-β dependent mechanisms.

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