Faculty Collaboration Database

Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension. Function (Oxf) 2023;4(5):zqad043

Date

08/23/2023

Pubmed ID

37609445

Pubmed Central ID

PMC10440998

DOI

10.1093/function/zqad043

Scopus ID

2-s2.0-85168790693 (requires institutional sign-in at Scopus site)

Abstract

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRR^RVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRR^RVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRR^RVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.

Author List

Mathieu NM, Fekete EM, Muskus PC, Brozoski DT, Lu KT, Wackman KK, Gomez J, Fang S, Reho JJ, Grobe CC, Vazirabad I, Mouradian GC Jr, Hodges MR, Segar JL, Grobe JL, Sigmund CD, Nakagawa P

Authors

Eva M. Fekete PhD Research Scientist I in the Physiology department at Medical College of Wisconsin
Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Matthew R. Hodges PhD Professor in the Physiology department at Medical College of Wisconsin
Gary C. Mouradian PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Pablo Nakagawa PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
John J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin
Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
Ibrahim Y. Vazirabad Bioinformatics Analyst III in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Desoxycorticosterone Acetate
Female
Hypertension
Mice
Receptors, Cell Surface
Renin
Sodium Chloride
Vasoconstrictor Agents