Role of renal VitD3 metabolism in atheroprotection

Activation of vitD3 metabolism by the kidney to produce 1,25(OH)2D3  might be a key protective mechanism in the prevention of atherosclerosis.

The metabolic syndrome (MetS) is a major and escalating clinical challenge worldwide. Western diet (WD) accounts largely for its development. MetS includes a cluster of cardiovascular risk factors, comprising insulin resistance, dyslipidaemia, hypertension, visceral obesity, and coronary heart disease. MetS also increases the risk of developing chronic kidney disease (CKD). In CKD patients, vitD deficiency is a strong predictor of accelerated renal disease progression and death. Higher amounts of vitD supplementation are required in CKD to achieve normal plasma 1,25(OH)2D3 values, the active compound that bind to vitD receptor (VDR). In humans, a loss of function mutation in the sterol 27-hydroxylase (CYP27A1) gene leads to cerebrotendinous xanthomatosis (CTX), characterized by a pronounced accumulation of cholesterol, cholestanol and bile alcohols in peripheral tissues, despite normal circulating cholesterol values. Severe atherosclerosis is a major complication leading to increased mortality at a young age. Mice with 50% reduced CYP27A1 activity also suffer from tremendous atherosclerosis when fed a WD.

We aim to analyse the contribution of renal CYP27A1 activity on VitD3 synthesis and metabolism and its contribution to the prevention of MetS and atherosclerosis.

The influence of renal function on vitD3 metabolism and atherosclerosis development will be investigated in an atherosclerotic mouse model, using the adenine-induced nephropathy. We will confirm our results in humans by quantifying VitD3 metabolites in patients with CKD and their age and sex matched controls. We will also measure the capacity of their plasma to efflux cholesterol and perform correlation analyses between these data and parameters of MetS (hypertension, dyslipidaemia, body mass index and plasma glucose).

These studies should clarify the role of CYP27A1 expression on VDR signalling in kidney and extra-renal tissues and its anti-atherosclerotic role.

PD Dr Geneviève Escher, Dr Sophia Verouti, PD Dr Michael Grössel