CCR5 deficiency does not reduce hypertensive end-organ damage in mice.

BACKGROUND: CCR5 is expressed on infiltrating T cells in hypertensive mice and CCR5 antagonists reduce hypertension making CCR5 an interesting target in treatment of hypertension. METHODS: To evaluate the role of CCR5 in hypertensive renal and cardiac end-organ damage, we induced hypertension with desoxycorticosterone acetate (DOCA) and angiotensin II (Ang II) in wild-type (WT) and CCR5-deficient mice. RESULTS: CCR5 expression was increased in renal cortex and cardiac tissue as measured by quantitative PCR. Systolic blood pressure and renal function did not differ between hypertensive CCR5(-/-) and WT mice. DOCA + Ang II induced massive albuminuria and glomerular injury but no difference was found between CCR5(-/-) and WT mice. In addition, no difference was found for renal inflammation as measured by infiltrating T cells, macrophages, and CCL2 expression. The renal expression of the CCR5 ligands, CCL3, and CCL5 was increased in the kidney of hypertensive mice. For CCL3 the increase was significantly higher in CCR5(-/-) than in WT mice. DOCA + Ang II induced cardiac damage as assessed by heart weight, cardiac fibrosis as well as expression of fetal and matrix components but no significant difference was found between CCR5(-/-) and WT mice. CONCLUSIONS: CCR5 deficiency does not influence hypertensive renal and cardiac end-organ damage. Cells that infiltrate by expression of CCR5 are either not pathogenic or CCR5-positive leukocytes can migrate via alternative chemokine receptors. Beneficial effects of CCR5 antagonists in hypertension are most likely due to unspecific effects of the antagonists. Possibly, other chemokine receptors in concert with CCR5 are important for hypertensive injury.

Pathogenic cycle between the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine and the leukocyte-derived hemoprotein myeloperoxidase.

BACKGROUND: The nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and the leukocyte-derived hemoprotein myeloperoxidase (MPO) are associated with cardiovascular diseases. Activation of monocytes and polymorphonuclear neutrophils (PMNs) with concomitant release of MPO is regulated in a nitric oxide-dependent fashion. The aim of the study was to investigate a potential 2-way interaction between ADMA and MPO. METHODS AND RESULTS: Ex vivo, ADMA uptake by isolated human PMNs, the principal source of MPO in humans, significantly impaired nitric oxide synthase activity determined by gas chromatography-mass spectrometry. In humans, short-term ADMA infusion (0.0125 mg · kg(-1) · min(-1)) significantly increased MPO plasma concentrations. Functionally, PMN exposure to ADMA enhanced leukocyte adhesion to endothelial cells, augmented NADPH oxidase activity, and stimulated PMN degranulation, resulting in release of MPO. In vivo, a 28-day ADMA infusion (250 µmol · kg(-1) · d(-1)) in C57Bl/6 mice significantly increased plasma MPO concentrations, whereas this ADMA effect on MPO was attenuated by human dimethylarginine dimethylaminohydrolase1 (hDDAH1) overexpression. Moreover, the MPO-derived reactive molecule hypochlorous acid impaired recombinant hDDAH1 activity in vitro. In MPO(-/-) mice, the lipopolysaccharide-induced increase in systemic ADMA concentrations was abrogated. CONCLUSIONS: ADMA profoundly impairs nitric oxide synthesis of PMNs, resulting in increased PMN adhesion to endothelial cells, superoxide generation, and release of MPO. In addition, MPO impairs DDAH1 activity. Our data reveal an ADMA-induced cycle of PMN activation, enhanced MPO release, and subsequent impairment of DDAH1 activity. These findings not only highlight so far unrecognized cytokine-like properties of ADMA but also identify MPO as a regulatory switch for ADMA bioavailability under inflammatory conditions.

Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice.

Angiotensin II (Ang II) activates at least two receptors, AT1 and AT2, with the majority of its effects-such as vasoconstriction, inflammation, and matrix deposition-mediated by the AT1 receptor. It is thought that the AT2 receptor counteracts these processes; however, recent studies have found proinflammatory and hypertrophic effects of this receptor subtype. To identify the physiological roles of the AT2 receptor in chronic kidney disease, we performed renal ablation in AT2 receptor knockout and wild-type mice. Renal injury caused a greater impairment of renal function, glomerular injury, albuminuria, and mortality in the knockout mice than in the wild-type mice. There was increased fibronectin expression and inflammation in the knockout mice, as shown by augmented monocyte/macrophage infiltration and higher chemokine monocyte chemotactic protein-1 (MCP-1) and RANTES expression in the remnant kidney. The higher mortality and renal morbidity of the knockout mice was not due to differences in systemic blood pressure, glomerular volume, AT1 receptor, renin, or endothelial nitric oxide synthase expression. Whether activation of the AT2 receptor will have therapeutic benefit in chronic kidney disease will require further study.