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Western diet induces renal artery endothelial stiffening that is dependent on the epithelial sodium channel.

Consumption of a western diet (WD) induces central aortic stiffening that contributes to transmittance of pulsatile blood flow to end organs including the kidney. Our recent work support that endothelial epithelial sodium channel (EnNaC) expression and activation enhances aortic endothelial cell stiffening through reductions in endothelial nitric oxide (NO) synthase (eNOS) and bioavailable NO that result in inflammatory/oxidant responses and perivascular fibrosis. However, the role that EnNaC activation has on endothelial responses in the renal circulation remain unknown. We hypothesized that cell-specific deletion of the α subunit of EnNaC would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. 28-week-old female αEnNaC KO and wild-type mice were fed either mouse chow or WD containing excess fat (46%), sucrose and fructose (17.5% each). WD feeding increased fat mass, indices of vascular stiffening in the aorta and renal artery (in vivo pulse wave velocity and ultrasound) and renal endothelial cell stiffening (ex vivo atomic force microscopy). WD further impaired aortic endothelial-dependent relaxation and renal artery compliance (pressure myography) without changes in blood pressure. WD-induced renal arterial stiffening occurred in parallel to attenuated eNOS activation, increased oxidative stress and aortic and renal perivascular fibrosis. αEnNaC deletion prevented these abnormalities and support a novel mechanism by which WDs contribute to renal arterial stiffening that is endothelial- and sodium channel-dependent. These results demonstrate that cell-specific EnNaC is important in propagating pulsatility into the renal circulation generating oxidant stress, reduced bioavailable NO and renal vessel wall fibrosis and stiffening.