The vascular protective effect of matrix Gla protein during kidney injury

Abstract

Matrix Gla protein (MGP) is a small secreted protein and requires vitamin K dependent γ-carboxylation for its function. MGP has been identified as a local inhibitor of vascular calcification because MGP-deficient mice die due to severe arterial calcification and resulting arterial rupture. Clinical trials revealed that reduction in active MGP predicts poor prognosis in patients due to cardiovascular complications. However, recent studies showed that MGP controls angiogenesis during development. MGP-deficient mice demonstrated abnormal hypervascularization and arteriovenous malformations in kidneys and other organs. This abnormal angiogenesis is largely caused by excessive expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR2). However, only a few studies have investigated the roles of MGP in tissue injury. We observed mesangial cell proliferation and mild interstitial fibrosis in addition to increased capillaries in kidneys of MGP-null mice even without injury. We also created a mouse model with kidney injury and found that kidney damage greatly increases MGP expression in peritubular capillary endothelial cells and tubular epithelial cells. Finally, our study showed that impairment of MGP expression aggravates peritubular capillary rarefaction and accumulation of collagen-producing myofibroblasts following kidney injury. Peritubular capillary damage induces capillary loss as well as trans-differentiation of vascular pericytes into myofibroblasts. These results indicate that MGP has the vascular protective effect in the injured kidney. Clinical trials have already started to test the efficacy of MGP activation to repair vascular calcification in patients with chronic kidney diseases. In this “Hypothesis and Theory” article, we discuss possible mechanisms by which MGP protects against vascular damage during tissue injury based on our experimental results and previous results from other research groups.

Extraocular muscle stem cells exhibit distinct cellular properties associated with non-muscle molecular signatures

“…EOM genes unique to the quiescent state included Tshr, encoding the thyroid-stimulating hormone receptor, which has been previously identified in bulk RNAseq as "EOM-resistant" kept upon engraftment into the limb (Evano et al, 2020b), and shown to control senescence in MuSCs of DMD rats (Taglietti et al, 2023). Matrix Gla protein (Mgp), which is a critical regulator of angiogenesis in multiple organs (Kida and Yamaguchi, 2022), was identified as exclusively upregulated in EOM cells upon activation (Figure 3H). Amongst the conserved EOM genes across cell states we identified Pitx2, a well-known major upstream regulator of EOM development (Gage et al, 1999b), Fos gene family members (Fos and Fosb), with Fos being recently identified in a subset of limb MuSCs with enhanced regenerative capacity (Almada et al, 2021), and Igfbp7, a specific marker of quiescent MuSCs that is downregulated upon activation (Fukada et al, 2007) but also reported to be upregulated in MuSCs upon exercise (Chen et al, 2020) (Figure 3F, Suppl Figure 3B, C).…”