High Phosphate and Low Protein Mediate Arterial and Cutaneous Vascular Calcification in CKD Mice

Background: Medial artery calcification and cutaneous arteriolar calcification are prevalent in patients with chronic kidney disease (CKD) and are strongly associated with increased morbidity and mortality. Current experimental CKD models, however, often fail to fully replicate the patterns of medial artery calcification and cutaneous arteriolar calcification, limiting our ability to elucidate their underlying molecular pathways. Developing a reliable experimental model for CKD-associated calcification and using it to identify therapeutic targets is essential for advancing treatment strategies for these vascular complications. In this study, we used a novel strategy that incorporated a high phosphate and low protein diet to promote medial artery and cutaneous vascular calcification in CKD mice. Methods: Mice underwent 5/6 nephrectomy and were then fed various diets. Vascular calcification was assessed using micro-CT scans, Alizarin Red staining, Von Kossa staining, and calcium assays. Kidney impairment and fibrosis were also evaluated. RNA sequencing (RNA-Seq) analysis was performed to identify key molecular pathways. The pharmacological inhibitor SB203580 was used to determine the significance of p38 MAPK signaling in vivo . Results: The high phosphate and low protein (HPi-Lp) diet markedly induced both medial artery and cutaneous vascular calcification in 5/6 nephrectomy mice while exacerbating kidney dysfunction and fibrosis. The p38 MAPK signaling was specifically highly activated. Pharmacological inhibition of p38 MAPK signaling significantly reduced medial artery and cutaneous vascular calcification as well as associated kidney fibrosis. Conclusions: The 5/6 nephrectomy CKD mouse model combined with a high phosphate and low protein diet effectively replicated medial artery and cutaneous arteriolar calcification.