Natriuretic Peptide Receptor C (NPR-C) emerges as direct tissue signaling modulator in cardiovascular-kidney-liver-metabolic syndrome

The cardiovascular-renal-liver-metabolic (CKLM) syndrome represents a complex integration of dysmetabolically driven heart, vascular, kidney, and liver diseases, sharing a common pathophysiological substrate. In obesity, upregulation of the clearance natriuretic peptide receptor C (NPR-C) in adipose tissue contributes to a functional 'NP deficiency,' undermining the protective cardiovascular and metabolic actions of endogenous natriuretic peptides. This deficiency highlights a critical gap in current therapeutic approaches, which often focus on systemic NP levels without fully addressing tissue-specific receptor dynamics. Understanding NPR-C's broader role is crucial for developing more targeted interventions.

This comprehensive review synthesizes current understanding of NPR-C biology within the Cardiovascular-Renal-Liver-Metabolic (CKLM) syndrome framework. Researchers analyzed preclinical and emerging human data to delineate NPR-C's dual function: its established role in natriuretic peptide clearance and its newly recognized capacity for direct intracellular signaling. The review integrates findings across various organ systems, including cardiac, renal, hepatic, and adipose tissues, to highlight NPR-C's context-dependent modulatory effects. The authors systematically compiled evidence demonstrating NPR-C's direct involvement in disease progression, independent of its clearance function.

The review highlights that NPR-C is upregulated in adipose tissue in obesity, leading to a functional 'NP deficiency' that compromises cardiovascular and metabolic protection. Crucially, it synthesizes evidence demonstrating NPR-C's direct intracellular signaling capabilities, independent of systemic natriuretic peptide levels. This signaling is triggered through interactions with specific ligands like CNP, musclin, and osteocrin. The review consolidates findings from experimental models where NPR-C directly modulates key pathological processes.

In experimental models, NPR-C directly modulates cardiac remodeling, podocyte injury, hepatic steatosis, vascular inflammation, and adipocyte dysfunction, showcasing its profound impact on tissue-specific pathologies within the CKLM syndrome context. This direct signaling suggests a more complex role for NPR-C in tissue homeostasis and disease progression than previously understood, offering new targets for intervention in CKLM syndrome.