AT1R autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability 2023

[pattismith]

AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability​

Maria A Pedrosa 1, Carmen M Labandeira 2, Rita Valenzuela 1, Aloia Quijano 3, Mariña Sanchez-Andrade 4, Juan A Suarez-Quintanilla 5, Jose L Lanciego 6, Jose L Labandeira-Garcia 7, Ana I Rodriguez-Perez 8

• PMID: 36535607
• DOI: 10.1016/j.bbi.2022.12.009

Free article

Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs).
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Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats.
Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease.
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Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls.
This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).

 

[pattismith]

The main pathology where AT1R and ETAR autoantibodies have recognized negative effect is chronic rejection after organ transplant, so it's interesting to follow what new articles says in this field:

Dysregulation of the mTOR signal pathway by agonistic antibodies against AT1- und ETA- receptor leads to disturbances in endothelial function

Wischnewski, Oskar

2021

The pathological hallmark of chronic rejection is the obliterative vasculopathy, which appears not only in rejection of organ transplants but also in preeclampsia, systemic sclerosis and antiphospholipid syndrome.

Autoantibodies against AT1R und ETAR might contribute to the pathogenesis of these diseases.

The mechanistic target of Rapamycin (mTOR) is an essential integrator of energy reserve and growth signals within cells and is responsible through its complex mTORC1 for cell proliferation and survival.

The mTOR complex 2 is responsible for the organisation of the actin cytoskeleton thereby regulating cell migration, chemotaxis, wound healing and endothelial functions.

An important connection between mTOR and the autoantibodies could be the MEK/ERK signal pathway.

The hypothesis of this study was that autoantibodies against AT1R und ETAR might cause a dysregulation of the mTOR signaling pathway resulting in impaired wound healing.

Microvascular endothelial cells were stimulated with sera from patients with high titers of AT1R und ETAR autoantibodies and the respective receptor blockers. Short- and long-time stimulation of the cells led to high phosphorylation of the mTORC1 target p70 S6 Kinase at threonine 389 and mTORC2 target AKT at serine 473.

The blockage of ERK did not abolish these mTORC activations while the use of PI3K blockers lowered the phosphorylation levels of both, mTORC1 and mTORC2.

Functionally, microvascular endothelial cells lost their wound healing ability in the presence of autoantibodies in a scratch assay. This was associated with hyperphosphorylation of AKT at Ser 473 as detected in immunofluorescent stainings.

Use of the non-specific mTOR inhibitor Rapamycin and the mTORC2-specific inhibitor MK 2205 restored the impaired wound healing.

These results clearly demonstrate the in vitro ability of AT1R / ETAR autoantibodies to dysregulate the mTOR pathway and its pathophysiological implications in impaired wound healing. This creates a rationale for the use of mTOR inhibitors in patients after kidney transplantation with high concentrations of AT1R und ETAR autoantibodies.

https://refubium.fu-berlin.de/handle/fub188/29234?locale-attribute=en