Lamin A is involved in the development of vascular calcification induced by chronic kidney failure and phosphorus load

- A high-phosphorus diet induced severe vascular calcification, decrease of renal function and higher mortality in uremic rats.
- Proteomics showed a distinct protein expression between non-calcified and calcified aortas, with lamin increase in the latter.
- VSMCs in calcifying media showed an increased binding of lamin with RUNX2, a major pro-osteoblastic transcription factor.
- Successful silencing of lamin prevented VSMCs' calcification and impaired the nuclear localization of RUNX2.
- Lamin A could play a key role in vascular calcification partly facilitating the nuclear localization of RUNX2.

Vascular calcification remains one of the main factors associated to morbidity and mortality in both ageing and chronic kidney disease. Both hyperphosphataemia, a well-known promoter of vascular calcification, and abnormal processing defects of lamin A/C have been associated to ageing. The main aim of this study was to analyse the effect of phosphorus load in the differential expression pattern of genes and proteins, particularly of lamin A/C, which are involved in phenotypic change of the vascular smooth muscle cells to osteoblast-like cells.The in vivo study of the calcified abdominal aortas from nephrectomized rats receiving a high phosphorus diet showed among others, a repression of muscle related proteins and overexpression of lamin A/C. Similar results were observed in vitro, where primary vascular smooth muscle cells cultured in calcifying medium showed increased expression of prelamin A and lamin A and abnormalities in the nuclear morphology. Co-immunoprecipitation assays showed novel and important physical interactions between lamin A and RUNX2 during the process of calcification. In fact, the knockdown of prelamin A and lamin A inhibited the increase of Runx2, osteocalcin and osteopontin gene expression, calcium deposition, nuclear abnormalities and the RUNX2 protein translocation into the nucleus of the cell.These in vivo and in vitro results highlight the important role played by lamin A in the process of vascular calcification.

Proposed model of the role of Lamin during the development of vascular calcification. Vascular smooth muscle cells (VSMCs) exposed to calcifying medium increase Prelamin/Lamin A levels, nuclear abnormalities and the interaction between RUNX2 and Lamin A, favouring the translocation of RUNX2 to the nucleus. These events induce the phenotype change, from VSMCs to “osteoblast-like” cells, as shown by the increase in Osteocalcin (Oc) and Osteopontin (Opn) expression and alkaline phosphatase (ALP) activity.Finally, all these alterations lead to vascular mineral deposition.111