High phosphorus and low protein mediate medial artery calcification and calcific uremic arteriolopathy in CKD mice: Significance of p38 MAPK signaling

Medial artery calcification and calcific uremic arteriolopathy (CUA) are observed in patients with chronic kidney disease (CKD). They are strongly associated with increased morbidity and mortality, yet the underlying mechanisms are poorly understood, and no effective drug targets have been developed. Herein, we observed that a high phosphate, low protein (HPi-Lp) diet induced medial artery and skin arteriolar calcification in 5/6 nephrectomy (5/6 Nx) CKD mice. We further determined that p38 MAPK signaling was critical in this vasculopathy. Calcification was examined using a micro-CT scan, Alizarin Red staining, Von Kossa staining, and calcium assay. Additionally, we found that the HPi-Lp diet feeding aggravated glomerulus impairment and renal fibrosis in 5/6 Nx mice. Using RNA-Seq analysis, we identified that p38 MAPK signaling was specifically activated in the 5/6 Nx-HPi-Lp mice. Inactivation of p38 MAPK signaling using a pharmacological inhibitor SB203580 significantly reduced medial artery calcification, skin arteriolar calcium deposits, and kidney fibrosis. Collectively, our data suggest that 5/6 Nx mice fed a HPi-Lp diet can be used as a reliable mouse model for studying medial artery and CUA arteriolar calcification. Additionally, targeting p38 MAPK signaling could be a promising therapeutic strategy to mitigate these vascular disorders in patients with CKD.