Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

Stegbauer, Johannes; Lee, Dong Hoon; Seubert, Silvia; Ellrichmann, Gisa; Manzel, Arndt; Kvakan, Heda; Müller, Dominik N.; Gaupp, Stefanie; Rump, Lars Christian; Gold, Ralf; Linker, Ralf A.

doi:10.1073/pnas.0903602106

Cited by 171 publications

(148 citation statements)

References 32 publications

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“…In the present study, aliskiren attenuated the intense pro-inflammatory profile in retina of Ren-2 rats with diabetes or OIR, with a reduction in leucostasis, ICAM-1 production and ED-1 immunolabelling to control levels. There is evidence that aliskiren reduced the macrophage content of atherosclerotic plaques [30], leucocyte adhesion in femoral arteries [31] and the number of CD11b + and CD11c + antigen presenting cells in a model of multiple sclerosis [32]. The results of the present study are consistent with these findings, and highlight the potent anti-inflammatory properties of aliskiren.…”

Section: Discussionsupporting

confidence: 82%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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Aim/hypothesis We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy. Methods Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg −1 day −1 , pump), or diabetic + lisinopril (10 mg kg −1 day −1 , drinking water) rats were evaluated over 16 weeks. For oxygeninduced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg −1 day −1 , pump) or lisinopril (10 mg kg −1 day −1 , drinking water) was administered during retinopathy development between postnatal days 12 and 18. Results Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg −1 day −1 aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg −1 day −1 aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg −1 day −1 aliskiren and normalised by 30 mg kg −1 day −1 aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels. Conclusions/interpretation Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

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Section: Discussionsupporting

confidence: 82%

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

et al. 2011

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“…Thus, it has been shown that deletion of immune cells or immune suppression therapy reduces Ang II-dependent hypertension and hypertensive end organ damage, respectively (3,4). In line with these results, recent studies have provided profound evidence that AT1 receptor inhibition directly affects immune cell function and thereby ameliorates the clinical course of experimental autoimmune encephalomyelitis (EAE) (5,6) or systemic lupus erythematosus (7,8).…”

supporting

confidence: 59%

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Hammer

Yang

Friedrich

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Recently, an alternative renin–angiotensin system pathway has been described, which involves binding of angiotensin-(1–7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II–mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.

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“…Several in vitro and in vivo studies have demonstrated that losartan inhibits DC activation (14,15,17). Elucidating the effects that losartan has on these factors may provide further insight into the pathology of inflammation, given that these factors are important in the development of LPS-induced ALI.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro and in vivo studies have shown that Ang II could induce DCs maturation (14,17). Additionally, several lines of evidence demonstrate that Ang II induces Th1 and Th17 immune responses and ultimately enhances inflammation in several Ang II-mediated inflammatory diseases (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

Zhang²,

Yu³

et al. 2011

Int J Mol Med

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Abstract. Acute lung injury (ALI) remains one of major causes of morbidity and mortality in intensive care medicine. The lack of efficient pharmacological interventions contributes to the high mortality rate of ALI. Losartan, an antagonist of angiotensin II (Ang II) type 1 receptor, is a potent therapeutic drug for ALI. Recent reports suggest that losartan inhibits the maturation of dendritic cells (DCs), impairs T-helper (Th) 1 immune response and ultimately attenuates inflammation in several Ang II-mediated inflammatory diseases. However, the possible protective mechanisms of losartan in ALI remain poorly understood. This study was aimed to define the effect of losartan on the frequency and phenotype of respiratory conventional DCs (cDCs) and Th cells polarization in lipopolysaccharide (LPS)-induced ALI mice. Results demonstrate that early after induction of LPS-induced ALI, cDCs expressing modest amounts of CD80 rapidly accumulated in the lungs. In addition, polarized Th1 and Th17 responses were markedly increased in LPS-induced ALI mice at 24 and 48 h. Of note, losartan led to inhibition of respiratory cDCs maturation at 6 h and suppressed Th1 and Th17 polarization responses compared with ALI mice at 24 and 48 h. Collectively, our findings may provide a novel and, at least, partial explanation for the protective effects by which losartan inhibits lung cDCs maturation and suppresses Th1 and Th17 immune responses.

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Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

Cited by 171 publications

References 32 publications

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

Role of the receptor Mas in macrophage-mediated inflammation in vivo

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

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