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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE288848 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Vascular calcification is a complex process and has been associated with aging, diabetes, chronic kidney disease (CKD). Although there have been several studies studying the role of miRNAs (miRs) in bone osteogenesis, little is known about the role of miRs in vascular calcification and their role in the pathogenesis of vascular abnormalities. Matrix vesicles (MV) are known to play an important role in initiating vascular smooth muscle cell (VSMC) calcification. In the present study, we performed miRNA microarray analysis to identify the dysregulated miRs between MV and VSMC derived from CKD rats to understand the role of post-transcriptional regulatory networks governed by these miRNAs in vascular calcification and to uncover the differential miRNA content of MV. The percentage of miRNA to total RNA was increased in MV compared to VSMC. Comparison of expression profiles of miRNA by microarray demonstrated 33 miRs to be differentially expressed with the majority (~ 57%) of them down-regulated. Target genes controlled by differentially expressed miRNAs were identified utilizing two different complementary computational approaches Miranda and Targetscan to understand the functions and pathways that may be affected due to the production of MV from calcifying VSMC thereby contributing to the regulation of genes by miRs. We found several processes including vascular smooth muscle contraction, response to hypoxia and regulation of muscle cell differentiation to be enriched. Signaling pathways identified included MAP-kinase and wnt signaling that have previously been shown to be important in vascular calcification. In conclusion, our results demonstrate that miRs are concentrated in MV from calcifying VSMC, and that important functions and pathways are affected by the miRs dysregulation between calcifying VSMC and the MV they produce. This suggests that miRs may play a very important regulatory role in vascular calcification in CKD by controlling an extensive network of post-transcriptional targets. Compare miRNA from matrix vesicles to miRNA from vascular smooth muscle cells that gave rise to the matrix vesicles from 3 sets of MV and VSMC derived from 3 normal and 3 CKD rats

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

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