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Updated: Jun 27, 2026
Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
Expression of gremlin, a bone morphogenetic protein antagonist,is associated with vascular calcification in uraemia
Aquiles Jara1, Cecilia Chacón, María Eugenia Burgos
1Department of Nephrology, School of Medicine, Universidad Católica de Chile, Lira 85, Santiago, Chile. ajara@med.puc.cl
Insights
Gremlin is overexpressed in vascular calcification in chronic kidney disease patients and rats. This suggests gremlin may play a role in the pathogenesis of vascular calcification in uremia.
Area of Science:
- Nephrology
- Cardiovascular Research
- Biochemistry
Background:
- Vascular calcification is a key risk factor for cardiovascular disease in chronic kidney disease (CKD) patients.
- Bone morphogenetic protein-7 (BMP-7) may decrease vascular calcification, while BMP-2 might promote it.
- Gremlin, an antagonist of bone morphogenetic proteins, is implicated in vascular calcification pathogenesis.
Purpose of the Study:
- To investigate the role of gremlin in vascular calcification associated with CKD.
- To examine gremlin expression in uraemic rats and human CKD patients with vascular calcification.
Main Methods:
- Gremlin, BMP-7, BMP-2, and BMPR2 expression were analyzed using in situ hybridization and immunohistochemistry.
- Vascular calcification was assessed using the von Kossa staining method.
- Studies were conducted on sham-operated and nephrectomized rats treated with calcitriol, and on human kidney transplant recipients.
Main Results:
- Uraemic rats with calcitriol treatment showed severe vascular calcification and marked gremlin overexpression in aortic media.
- Gremlin expression correlated with BMP-2 and BMPR2 levels in rats.
- Human CKD patients exhibited significantly higher gremlin expression in vascular media compared to controls.
Conclusions:
- A significant overexpression of gremlin was observed in the vasculature of uraemic rats and patients with vascular calcification.
- Gremlin may play a role in the vascular calcification process in uraemia.
- The precise interaction of gremlin with BMP-7 or BMP-2 requires further investigation.
Background:
Vascular calcification has been widely recognized as a significant contributor to cardiovascular risk in patients with chronic kidney disease. Recent evidence suggests that BMP-7 decreases the vascular calcification observed in uraemic rats, while BMP-2 could also be participating in this process. Gremlin, a bone morphogenetic protein antagonist, has been detected in rat aortic vascular smooth muscle cells (VSMCs), and since the role of the VSMCs into vascular calcification in uraemia is considered critical in this process, we hypothesized that gremlin could be participating in its pathogenesis. With this aim, we studied its expression in aorta from uraemic rats with calcitriol-induced vascular calcification and in 16-vessel biopsies of uraemic patients undergoing kidney transplantation.
Methods:
Gremlin was detected by in situ hybridization (ISH) and immunohistochemistry (IMH). BMP-7, BMP-2 and BMP-2 receptor (BMPR2) were detected by IMH. Vascular calcification was assessed by the von Kossa staining method. Sham-operated and 5/6 nephrectomized rats (NFX) (1.2%P) were treated with vehicle or calcitriol (80 ng/kg, intraperitoneally every other day). Rats were killed after 4 weeks of treatment, and abdominal aorta was dissected for assessment of gremlin expression and vascular calcification. Epigastric arteries were obtained from dialysis patients during kidney transplantation procedure. Arteries from kidney donors were also studied.
Results:
NFX rats developed a mild vascular calcification, whereas NFX-calcitriol rats developed a severe vascular and tissue calcification. A marked overexpression of gremlin was observed in the vascular media of aorta from NFX-calcitriol rats as compared with NFX and sham-calcitriol groups (4.8 +/- 1.3 versus 0.59 +/- 0.17 versus 0.19 +/- 0.07 percentage/mm(2), P < 0.01), and correlated with the BMP-2 and BMPR2 expression. Sham rats showed minimal or null gremlin expression. BMP-7 was not found in sham or calcified arteries. In human studies, we observed strong expression of gremlin mRNA and protein in the media layer of vessels from uraemic patients as compared with those from normal humans (staining score 3.72 +/- 0.95 versus 0.91 +/- 0.08 percentage/mm(2), P < 0.05).
Conclusion:
We observed a marked gremlin overexpression in the media layer of vessels in uraemic rats and patients in association with vascular calcification and BMP-2 expression. We postulate that gremlin may play a role in the vascular calcification process in uraemia, and its interaction with BMP-7 or BMP-2 remains to be elucidated.
