Shen-Gu-Mai-Kang Formula alleviates CKD-associated vascular calcification by suppressing VSMC osteogenic transdifferentiation via the Sfrp2/β-catenin signaling.

BACKGROUND

Vascular calcification (VC) is a life-threatening complication of chronic kidney disease (CKD) characterized by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Shen-Gu-Mai-Kang (SGMK), a patented Chinese herbal formula, shows clinical efficacy against CKD-VC. However, the mechanism of SGMK alleviating VC remain to be fully elucidated.

PURPOSE: To evaluate SGMK's therapeutic effects on CKD-VC and decipher its underlying molecular targets.

METHODS

CKD-VC mouse model was established to assess SGMK's systemic effects. Chemical profiling was performed via UHPLC-Q-Orbitrap. Aortic RNA-seq, virtual screening, and lentivirus-mediated knockdown were integrated to identify and validate the core target of SGMK. Candidate hits were validated using Pi-induced VSMCs calcification in vitro.

RESULTS

SGMK significantly ameliorated renal dysfunction, hyperphosphatemia, and aortic calcium deposition in CKD mice. Furthermore, it effectively prevented osteoporosis, demonstrating a holistic modulation of the kidney-bone-vascular axis. RNA-seq identified Sfrp2 as a pivotal target of SGMK. Chemical profiling and virtual screening revealed that baicalin and luteolin exhibited high binding affinities and structural stability with Sfrp2. Mechanistically, SGMK and its key components inhibited the osteogenic transdifferentiation of VSMCs by regulating Sfrp2 and suppressing the activation of the β-catenin signaling pathway, evidenced by Sfrp2 knockdown experiments.

CONCLUSION

SGMK alleviates CKD-associated VC by targeting the Sfrp2/β-catenin axis. Baicalin and luteolin are identified as the primary bioactive markers responsible for SGMK's efficacy, providing a scientific rationale for its clinical use in managing CKD-VC.