A molecular target of vascular calcification in chronic kidney disease.

Mohamed G Atta

doi:10.1172/jci156257

Abstract

Vascular calcification (VC) causes cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those with end-stage kidney disease (ESKD) on maintenance dialysis treatment. Although many mechanisms have been proposed, their detailed effects remain incompletely understood. In this issue of the JCI, Li et al. examined the molecular mechanism of the protective role of SIRT6 in VC in patients with CKD. Using in vitro and animal models of CKD, the authors demonstrated that SIRT6 prevents VC by suppressing the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Mechanistically, SIRT6 bound and deacetylated the runt-related transcription factor 2 (Runx2), a key transcription factor for osteogenic differentiation, promoting its nuclear export for proteasome degradation. These studies provide a pathway in the pathogenesis of VC and justify investigating SIRT6 as a potential target in CKD.

Highlights

Vascular calcification (VC) involves the deposition of calcium phosphate mineral along with the local expression and deposition of bone-associated, mineralization-regulating proteins at two distinct sites of the blood vessel: the intima and the media [1]
Maintenance of normal serum phosphate levels depends on two phosphaturic hormones: fibroblast growth factor 23 (FGF23), secreted by bone osteocytes, and parathyroid hormones (PTH), released from the parathyroid gland
PTH binds to the PTH type 1 receptor on the basolateral membrane of the proximal tubular cells, inducing the retrieval of sodium phosphate transporter 2a (NPT2a) from the brush border

Summary

Introduction

Vascular calcification (VC) involves the deposition of calcium phosphate mineral along with the local expression and deposition of bone-associated, mineralization-regulating proteins at two distinct sites of the blood vessel: the intima and the media [1]. FGF23 and its cofactor klotho bind to the klotho-FGFR1c complex on the basolateral membrane of the proximal tubular cells, which decreases the expression of both sodium phosphate cotransporters NPT2a and NPT2c. Regulation is shown by the development of vascular and ectopic calcifications and the short lifespan in klotho-deficient mice or double knockout of both klotho and FGF23 in mice on a high-phosphate diet [3, 4].

Results

Conclusion