Identification and Characterization of Minerization Mediators Derived From Adrenal Glands

Journal of the American Society of Nephrology, vol. 33, pp. 97

Abstract

Background: Mineralization of vascular tissue is a common symptom of chronic kidney disease and is accompanied by a reduction in bone mineralization and density. In the current study, we investigated a novel systemic regulation of vascular mineralization processes by adrenal glands. Methods: Bovine adrenal gland were homogenized and separated by chromatographic fractionation. The resulting fractions were assessed in cells, thoracic aortic rings and vitamin D3-nicotine renal failure rat model to study their effects on vascular and bone mineralization processes. Potential mediators were identified by mass spectrometry in compliment with pertinent databases. Results: We identified a novel peptide from bovine adrenal glands that inhibits transdifferentiation of aortic smooth muscle cells into osteoblast like cells, thereby hindering vascular mineralization. This peptide named ‘Calcification Blocking Factor’ (CBF) based on its protective effects against vascular mineralization is released from chromogranin A through enzymatic cleavage by calpain 1 and kallikrein. CBF reduced calcium content of aortic smooth muscle cells and thoracic aortic rings treated under calcifying culture conditions and in aortas from vitamin D3-nicotine (VDN) animals. CBF prevented aortic smooth muscle cell transdifferentiation into osteoblast-like cells in the vessel wall via the PIT-1 sodium-dependent phosphate transporter, inhibiting NF-χB activation and its downstream BMP2/p-SMAD signaling. CBF treated VDN animals showed a significantly lower pulse pressure which is a marker of arterial stiffness. Consistent with our preclinical results, concentration of CBF was found to be significantly reduced in patients with chronic kidney disease who are predisposed to vascular mineralization. Smaller fragments of the 19 aa peptide were analyzed to identify the active site of CBF. Conclusions: In conclusion, we identified a novel peptide derived from adrenal glands which modulates vascular mineralization. Additionally, we identified smaller peptides that reduces vascular calcification by inhibiting smooth muscle cell transdifferentiation. These findings suggest a novel function of adrenal glands in calcium mineralization. Funding: Government Support - Non-U.S.

Authors 5

1. Shruti Bhargava Aachen

   Maastricht University · Universitätsklinikum Aachen

   Affiliation as printed

   Universitatsklinikum Aachen Institut fur Molekulare Herz Kreislauf Forschung, Aachen, Germany

   Universiteit Maastricht Cardiovascular Research Institute Maastricht, Maastricht, Netherlands

2. Vera Jankowski Aachen

   Universitätsklinikum Aachen

   Affiliation as printed

   Universitatsklinikum Aachen Institut fur Molekulare Herz Kreislauf Forschung, Aachen, Germany

3. Jonas Laget
   Affiliation as printed

   RD Nephrologie, Montpellier, France

4. Bernard F. Jover
   Affiliation as printed

   RD Nephrologie, Montpellier, France

5. Joachim Jankowski Aachen

   Maastricht University · Universitätsklinikum Aachen

   Affiliation as printed

   Universitatsklinikum Aachen Institut fur Molekulare Herz Kreislauf Forschung, Aachen, Germany

   Universiteit Maastricht Cardiovascular Research Institute Maastricht, Maastricht, Netherlands