Bile Acid Signaling as an Upstream Modulator of RAAS and Chloride Homeostasis, V 1.1, February 2026

The renin–angiotensin–aldosterone system (RAAS) is classically described as a renal pressure–volume regulatory cascade initiated by renin release and propagated through angiotensin signaling. In parallel, bile acids function as systemic signaling molecules acting through the nuclear receptor farnesoid X receptor (FXR; NR1H4) and the membrane receptor TGR5 (GPBAR1), with established roles in hepatic, vascular, and renal physiology. Increasing preclinical evidence indicates that renal and vascular FXR activation attenuates hypertensive phenotypes, modulates nitric oxide signaling, and alters RAAS-related pathways. Direct suppression of renin gene transcription is demonstrated primarily in animal and cell models, whereas human data more clearly support FXR-mediated shifts in vascular receptor balance (e.g., AT2R regulation) and renal injury pathways commonly driven by RAAS activation. This note proposes a mechanistic continuity model: bile acid receptor signaling may function as an upstream modulator of RAAS tone, with downstream implications for renal tubular transport, chloride handling, and acid–base balance. While causal human renin-transcription evidence remains limited, the convergence of hepatic–vascular–renal FXR/TGR5 signaling provides a plausible framework for understanding oscillatory blood pressure patterns and hyperchloremic, non–anion gap metabolic disturbances observed in certain clinical phenotypes. The objective is not to redefine RAAS biology, but to clarify cross-system regulatory intersections and generate testable hypotheses linking bile acid signaling, RAAS biomarkers, and chloride/bicarbonate trends. Related WorkThis mechanistic note aligns with a growing body of research examining cross-talk between bile acid receptor signaling and cardiovascular–renal regulation. It also situates within a broader systems framework exploring electrolyte regulation, RAAS modulation, and chloride-dominant acid–base patterns. Expanded integrative modeling of hierarchical endocrine and fluid regulatory dynamics is developed in related preprints by the author; however, the present paper is intended as a standalone physiologic continuity analysis grounded in established literature.