PKCα/TGF-β signalling axis: A novel therapeutic target for arterial medial calcification

Arterial medial calcification (AMC) is associated with increased cardiovascular mortality in chronic kidney disease (CKD) patients; no treatments exist.

We reported previously that knocking-down PKCα in vascular smooth muscle cells (VSMCs) increases calcification in vitro.

Our latest data provide the first direct evidence that uraemia-induced AMC is also increased in PKCα-/- mice in vivo, and crucially, PKCα appears to exert these effects by increasing pro-calcific transforming growth factor-β (TGF-β) signalling in VSMCs; TGF-β/SMAD2 signalling is also upregulated in arteries from CKD patients.

PKCα-/- mice exhibit greater renal dysfunction following 5/6 nephrectomy than wild-types, but there is no correlation between blood urea nitrogen levels and the extent of calcification in these mice.

We now propose to: (i) determine the mechanism by which PKCα modulates TGF-β signalling in VSMCs; (ii) confirm whether loss of PKCα enhances uraemia-induced AMC by increasing TGF-β signalling in vivo; (iii) investigate whether activating PKCα reduces VSMC calcification; (iv) determine whether the PKCα and TGF- signalling pathways are dysregulated in arteries from CKD patients, and whether this correlates with the extent of calcification.

These timely studies are an essential pre-requisite to pre-clinical studies to determine whether the PKCα/TGF-β axis is a potential new drug target for AMC.