1. ¹Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki, Japan
2. ²Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan
3. ³Division of Cardiology, Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan
4. ⁴Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan

Correspondence: Professor A Fukamizu, PhD, Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, Centre for Tsukuba Advanced Research Alliance, University of Tsukuba, Ten-noudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan. E-mail: akif@tara.tsukuba.ac.jp

Received 26 September 2007; Revised 3 March 2008; Accepted 7 March 2008; Published online 19 May 2008.

Abstract

The renin–angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RAS-activated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout' (KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.