The NADPH Link between the Renin Angiotensin System and the Antioxidant Mechanisms in Dopaminergic Neurons

Rafael Franco; Joan Serrano-Marín; Gemma Navarro; Rafael Rivas-Santisteban

doi:10.3390/antiox12101869

The NADPH Link between the Renin Angiotensin System and the Antioxidant Mechanisms in Dopaminergic Neurons

Antioxidants (Basel). 2023 Oct 16;12(10):1869. doi: 10.3390/antiox12101869.

Authors

Rafael Franco^{1

2

3}, Joan Serrano-Marín¹, Gemma Navarro^{2

4

5}, Rafael Rivas-Santisteban^{2

6}

Affiliations

¹ Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, 08028 Barcelona, Spain.
² CiberNed, Network Center for Neurodegenerative Diseases, Spanish National Health Institute Carlos III, 28029 Madrid, Spain.
³ School of Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain.
⁴ Department of Biochemistry and Physiology, School of Pharmacy and Food Science, Universitat de Barcelona, 08028 Barcelona, Spain.
⁵ Institute of Neurosciences, Universitat de Barcelona, 08007 Barcelona, Spain.
⁶ Campus Bellaterra, Autonomous University of Barcelona, Cerdanyola del Vallés, 08193 Barcelona, Spain.

Abstract

The renin angiotensin system (RAS) has several components including signaling peptides, enzymes, and membrane receptors. The effort in characterizing this system in the periphery has led to the approval of a class of antihypertensives. Much less is known about RAS in the central nervous system. The production of RAS peptides and the expression of several RAS enzymes and receptors in dopaminergic neurons of the substantia nigra has raised expectations in the therapy of Parkinson's disease, a neurodegenerative condition characterized by lack of dopamine in the striatum, the motor control region of the mammalian brain. On the one hand, dopamine production requires reducing power. On the other hand, reducing power is required by mechanisms involved in REDOX homeostasis. This review focuses on the potential role of RAS in the regulation of neuronal/glial expression of glucose-6-phosphate dehydrogenase, which produces the NADPH required for dopamine synthesis and for reactive oxygen species (ROS) detoxification. It is known that transgenic expression of the gene coding for glucose-6-phosphate dehydrogenase prevents the death of dopaminergic nigral neurons. Signaling via angiotensin II G protein-coupled receptors, AT₁ or AT₂, leads to the activation of protein kinase A and/or protein kinase C that in turn can regulate glucose-6- phosphate dehydrogenase activity, by Ser/Thr phosphorylation/dephosphorylation events. Long-term effects of AT₁ or AT₂ receptor activation may also impact on the concentration of the enzyme via activation of transcription factors that participate in the regulation of gene expression in neurons (or glia). Future research is needed to determine how the system can be pharmacologically manipulated to increase the availability of NADPH to neurons degenerating in Parkinson's disease and to neuroprotective glia.

Keywords: 6-phospho-gluconate dehydrogenase; MAS receptors; NADPH; Parkinson’s disease; angiotensin receptors; brain; glucose-6-phosphate dehydrogenase; glutathione; neuromelanin; substantia nigra.

Publication types

Review

Grants and funding

This work was supported by grants PID2020-113430RB-I00 and PID2021-126600OB-I00 funded by Spanish MCIN/AEI/10.13039/501100011033 and, as appropriate, by “ERDF A way of making Europe”, by the European Union or by the European Union Next Generation EU/PRTR. The research group of the University of Barcelona is considered to be “of excellence” (grup consolidat 2021 SGR 00304) by the Regional Catalonian Government.