Agonist autoantibodies against the angiotensin AT1 receptor in renal and hypertensive disorders

Walther, Thomas; Stepan, Holger

doi:10.1007/s11906-007-0023-5

Cited by 13 publications

(9 citation statements)

References 42 publications

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“…31, 32 It is not clear whether AT1RaAbs are specific disease-causing agents, or if their levels reflect age-related global dysregulation of autoantibody production. Autoantibodies in general are capable of stimulating receptors and causing disease, such as Graves’ disease 33 and dilated cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Agonistic Angiotensin Receptor Autoantibodies as Biomarkers of Adverse Outcomes

et al. 2017

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Background Agonistic angiotensin II type I receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be utilized to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker (ARB) treatment. Methods Demographic and physiologic covariates were measured in a discovery set of community dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of ARB treatment. Results The Baltimore group had 28 subjects with falls, 32 frail subjects and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6 (Spearman r = 0.33, P < 0.0001), systolic BP (Spearman r = 0.28, P < 0.0001), body mass index (Spearman r = 0.28, P < 0.0001), weaker grip strength (Spearman r = −0.34, P < 0.01), and slower walking speed (Spearman r = −0.30, P < 0.05). Individuals with high AT1RaAbs were 3.9 (95% CI 1.38–11.0) times more likely to be at high risk after adjusting for age (P<0.05).Every 1 µg/ml increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, gender, BMI and BP. TThe Chicago groupgroup had 46 subjects with falls and 60 deaths.. Serum AT1RaAb levels were significantly correlated with grip strength (Spearman r = −0.57, P < 0.005), walking speed (Spearman r = −0.47, P< 0.005) and falls (Spearman r = 0.30, P < 0.05). Every 1 µg/ml increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, gender, BMI and BP. Chronic treatment with ARBs was associated with better control of systolic BP and attenuation of decline in both grip strength and time to death. Conclusions In older individuals, higher AT1RaAb levels were associated with inflammation, hypertension and adverse outcomes. ARB treatment may blunt the harm associated with high levels of AT1RaAb.

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Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Agonistic Angiotensin Receptor Autoantibodies as Biomarkers of Adverse Outcomes

et al. 2017

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“…Considering the agonistic function of an antibody when it cross-links its target, the mechanism of action may depend on the signaling capacity and biological function of the ligand as with HLA I molecules. For example, angiotensin II receptor AT1 autoantibodies are well-established agonists, which promote hypertension and may contribute to renal allograft rejection [146–148]. Antibodies from autoimmune sera upregulate adhesion molecules and cytokines on endothelial cells [149–151], but when the target is unknown the precise mechanism remains elusive.…”

Section: Non-hla Antibodiesmentioning

confidence: 99%

Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury

Valenzuela

Reed

2013

Methods in Molecular Biology

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Until recently, allograft rejection was thought to be mediated primarily by alloreactive T cells. Consequently, immunosuppressive approaches focused on inhibition of T cell activation. While short-term graft survival has significantly improved and rejection rates have dropped, acute rejection has not been eliminated and chronic rejection remains the major threat to long-term graft survival. Increased attention to humoral immunity in experimental systems and in the clinic has revealed that donor specific antibodies (DSA) can mediate and promote acute and chronic rejection. Herein, we detail the effects of alloantibody, particularly HLA antibody, binding to graft vascular and other cells, and briefly summarize the experimental methods used to assess such outcomes.

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“…However, abnormal autoimmune response is a pathogenic factor contributing to and promoting the occurrence of cardiovascular diseases [5]. Since Wallukat el al [6] detected AT1-AA in the serum of preeclamptic patients in 1999, AT1-AA have been detected in the serum of patients with various cardiovascular diseases and those who underwent kidney transplantation [7]. Xia et al reported that AT1-AA were detectable six weeks earlier in the serum of patients with reduced uterine perfusion as compared with the preeclamptic patients.…”

Section: Introductionmentioning

confidence: 99%

Antibodies against AT1 Receptors Are Associated with Vascular Endothelial and Smooth Muscle Function Impairment: Protective Effects of Hydroxysafflor Yellow A

et al. 2013

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Ample evidence has shown that autoantibodies against AT1 receptors (AT1-AA) are closely associated with human cardiovascular disease. The aim of this study was to investigate mechanisms underlying AT1-AA-induced vascular structural and functional impairments in the formation of hypertension, and explore ways for preventive treatment. We used synthetic peptide corresponding to the sequence of the second extracellular loop of the AT1 receptor (165–191) to immunize rats and establish an active immunization model. Part of the model received preventive therapy by losartan (20 mg/kg/day) and hyroxysafflor yellow A (HSYA) (10 mg/kg/day). The result show that systolic blood pressure (SBP) and heart rate (HR) of immunized rats was significantly higher, and closely correlated with the plasma AT1-Ab titer. The systolic response of thoracic aortic was increased, but diastolic effects were attenuated markedly. Histological observation showed that the thoracic aortic endothelium of the immunized rats became thinner or ruptured, inflammatory cell infiltration, medial smooth muscle cell proliferation and migration, the vascular wall became thicker. There was no significant difference in serum antibody titer between losartan and HSYA groups and the immunized group. The vascular structure and function were reversed, and plasma biochemical parameters were also improved significantly in the two treatment groups. These results suggest that AT1-Ab could induce injury to vascular endothelial cells, and proliferation of smooth muscle cells. These changes were involved in the formation of hypertension. Treatment with AT1 receptor antagonists and anti oxidative therapy could block the pathogenic effect of AT1-Ab on vascular endothelial and smooth muscle cells.

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Agonist autoantibodies against the angiotensin AT1 receptor in renal and hypertensive disorders

Cited by 13 publications

References 42 publications

Discovery and Validation of Agonistic Angiotensin Receptor Autoantibodies as Biomarkers of Adverse Outcomes

Discovery and Validation of Agonistic Angiotensin Receptor Autoantibodies as Biomarkers of Adverse Outcomes

Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury

Antibodies against AT1 Receptors Are Associated with Vascular Endothelial and Smooth Muscle Function Impairment: Protective Effects of Hydroxysafflor Yellow A

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