Contrasting Effects of Systemic Monocyte/Macrophage and CD4+ T Cell Depletion in a Reversible Ureteral Obstruction Mouse Model of Chronic Kidney Disease
Using a reversible UUO model (rUUO), we have demonstrated that C57BL/6 mice are susceptible to development of CKD after obstruction-mediated kidney injury while BALB/c mice are resistant. We hypothesized that selective systemic depletion of subpopulations of inflammatory cells during injury or repair might alter the development of CKD. To investigate the impact of modification of Th-lymphocytes or macrophage responses on development of CKD after rUUO, we used an anti-CD4 antibody (GK1.5) or liposomal clodronate to systemically deplete CD4+ T cells or monocyte/macrophages, respectively, prior to and throughout the rUUO protocol. Flow cytometry and immunohistochemistry confirmed depletion of target cell populations. C57BL/6 mice treated with the GK1.5 antibody to deplete CD4+ T cells had higher BUN levels and delayed recovery from rUUO. Treatment of C57BL/6 mice with liposomal clodronate to deplete monocyte/macrophages led to a relative protection from CKD as assessed by BUN values. Our results demonstrate that modulation of the inflammatory response during injury and repair altered the susceptibility of C57BL/6 mice to development of CKD in our rUUO model. 1. Introduction Between 10 and 16% of the adult population worldwide is affected by chronic kidney disease (CKD) [1]. From the periods of 1988–1994 to 2005–2010 the prevalence of CKD in the United States rose from 12.3 to 14.0 percent. The largest relative increase, from 25.4 to 40.8 percent, was seen in those with cardiovascular disease [2]. The life expectancy for a 50-year-old adult in the United States is 35.5 years; this decreases by 7.5 years in the presence of CKD [2]. From among a variety of possible rodent models of CKD, the unilateral ureteral obstruction (UUO) model has become widely used to evaluate features of renal injury [3–5]. Advantages of the UUO model include the fact that kidney injury and fibrosis occur over a time course of days to weeks and that the model can be used in mice of any strain. Typically in the UUO model, obstruction is achieved by irreversible ligation of the ureter. Importantly, functional consequences of kidney injury cannot be assessed using irreversible obstruction and findings must be interpreted in the context of ongoing injury from obstruction. To model CKD in mice we generated a reliable reversible UUO model (rUUO) [6]. This model combines several key advantages for studying development and progression of CKD, including assessment of functional consequences of kidney injury using biomarkers such as blood urea nitrogen (BUN) measurements and the ability to
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