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Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3150-3156. doi: 10.1073/pnas.1909124117. Epub 2020 Jan 28.

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

Author information

1
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, 305-8577 Tsukuba, Japan.
2
Department of Nephrology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575 Tsukuba, Japan.
3
Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
4
Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572 Tsukuba, Japan.
5
Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572 Tsukuba, Japan.
6
Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Ibaraki 305-8577 Tsukuba, Japan.
7
Department of Engineering, School of Medicine, Tohoku University, Aoba-ku, 980-8775 Sendai, Japan.
8
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, 305-8577 Tsukuba, Japan; akif@tara.tsukuba.ac.jp.
9
The World Premier International Research Center Initiative (WPI), International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8577 Tsukuba, Japan.

Abstract

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

KEYWORDS:

H3 agonist; animal model; anti-inflammation; cardiorenal damages; histamine

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