Mediterranean G6PD Variant Rats Are Protected From Angiotensin II-Induced Hypertension and Kidney Damage, but Not From Inflammation and Arterial Stiffness

Authors

Shun Matsumura, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.
Catherine D'Addiaro, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.
Orazio J. Slivano, Department of Medicine, Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, United States of America.
Carmen De Miguel, Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America.
Charles Stier, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.Follow
Rakhee Gupte, Raadysan Inc., Fishkill, NY 12524, United States of America.
Joseph M. Miano, Department of Medicine, Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, United States of America.
Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America. Electronic address: sachin_gupte@nymc.edu.Follow

Author Type(s)

Faculty

DOI

10.1016/j.vph.2022.107002

Journal Title

Vascular Pharmacology

First Page

107002

Document Type

Article

Publication Date

8-1-2022

Department

Pharmacology

Abstract

RATIONALE: Epidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model. OBJECTIVE: To determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PD) variant and in wild-type (WT) rats. METHODS AND RESULTS: Our findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PD than in WT rats. Additionally, Ang-II induced less glomerular and tubular damage in the kidneys - a consequence of elevated pressure - in G6PD than WT rats. However, Ang-II-induced arterial stiffness increased in G6PD and WT rats, and there were no differences between the groups. Mechanistically, we found aorta of G6PD as compared to WT rats produced less sustained contraction and less inositol-1,2,3-phosphate (IP3) and superoxide in response to Ang-II. Furthermore, aorta of G6PD as compared to WT rats expressed lower levels of phosphorylated extracellular-signal regulated kinase (ERK). Interestingly, the aorta of G6PD as compared to WT rats infused with Ang-II transcribed more (50-fold) myosin heavy chain-11 (MYH11) gene, which encodes contractile protein of smooth muscle cell (SMC), and less (2.3-fold) actin-binding Rho-activating gene, which encodes a protein that enhances SMC proliferation. A corresponding increase in MYH11 and Leiomodin-1 (LMOD1) staining was observed in arteries of Ang-II treated G6PD rats. However, G6PD deficiency did not affect the accumulation of CD45 cells and transcription of genes encoding interleukin-6 and collagen-1a1 by Ang-II. CONCLUSIONS: The G6PD loss-of-function variant found in humans protected rats from Ang-II-induced HTN and kidney damage, but not from vascular inflammation and arterial stiffness.

Recommended Citation

Matsumura, S., D'Addiaro, C., Slivano, O. J., De Miguel, C., Stier, C., Gupte, R., Miano, J. M., & Gupte, S. A. (2022). Mediterranean G6PD Variant Rats Are Protected From Angiotensin II-Induced Hypertension and Kidney Damage, but Not From Inflammation and Arterial Stiffness. Vascular Pharmacology, 145, 107002. https://doi.org/10.1016/j.vph.2022.107002