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Therapeutic Strategies Targeting the Kidney-Liver-Immune-Heart Network: Circadian and Mechanosensory Pathways in
Yuya Yoshida1, Kohei Fukuoka1, Tomohito Tanihara1
1Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
Abstract:
The present review discusses vitamin A/retinoid metabolism as a cross-organ axis in which hepatic clock-dependent retinoid handling may affect immune clock gene expression through the stimulation of retinoic acid 6-Janus kinase 2-signal transducer and activator of transcription 5 signaling, potentially promoting pro-inflammatory monocyte states. We further highlight mechanosensory signaling as a second convergent layer that integrates hemodynamic forces with tissue microenvironmental cues. Among these pathways, G protein-coupled receptor 68, a proton- and flow-sensitive G protein-coupled receptor, is discussed as a representative druggable node linking mechanical and inflammatory signaling in chronic kidney disease-associated cardiac injury. Finally, we outline potential therapeutic directions, including (i) circadian alignment/chronopharmacology, (ii) modulation of retinoid metabolism and signaling, and (iii) targeted inhibition of primary immune and mechanosensory effectors.
Insights
Hepatic clock-controlled vitamin A metabolism influences immune cell clock genes via retinoic acid signaling. Mechanosensory pathways, like G protein-coupled receptor 68, also link mechanical forces to inflammation in kidney disease-related heart injury.
Area of Science:
- Cardiovascular Biology
- Immunology
- Chronobiology
Background:
- Vitamin A (retinoid) metabolism involves a cross-organ axis influenced by the liver's circadian clock.
- Mechanosensory signaling integrates hemodynamic forces with tissue microenvironment cues.
- Chronic kidney disease (CKD) can lead to cardiac injury, involving complex signaling pathways.
Purpose of the Study:
- To review the role of hepatic retinoid metabolism in immune clock gene expression.
- To highlight mechanosensory signaling pathways in integrating mechanical and inflammatory cues.
- To discuss therapeutic strategies for CKD-associated cardiac injury.
Main Methods:
- Review of existing literature on retinoid metabolism, circadian rhythms, and mechanosensory signaling.
- Discussion of signaling pathways including Janus kinase 2-signal transducer and activator of transcription 5 (JAK2-STAT5).
- Focus on G protein-coupled receptor 68 (GPCR68) as a druggable target.
Main Results:
- Hepatic clock-dependent retinoid handling may promote pro-inflammatory monocyte states via retinoic acid-JAK2-STAT5 signaling.
- Mechanosensory signaling, exemplified by GPCR68, links mechanical forces to inflammation.
- GPCR68 is identified as a key node in CKD-associated cardiac inflammation.
Conclusions:
- Circadian alignment, retinoid metabolism modulation, and targeted inhibition of immune/mechanosensory pathways are potential therapeutic avenues.
- Understanding the interplay between retinoid metabolism, circadian clocks, and mechanosensing is crucial for treating inflammatory conditions.
- Targeting GPCR68 offers a potential strategy for mitigating cardiac injury in CKD.
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