Connecting salt appetite to cardiovascular and kidney disease

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Reducing salt intake is a major health policy advocated by The World Health Organization to reduce the global burden of hypertension, Cardiovascular Disease and Chronic Kidney Disease (CKD). Salt restriction is a beneficial lifestyle change for people with cardiovascular and kidney disease but long-term adherence to reduced salt intake is poor. In CVD/CKD patients, this may reflect abnormal salt perception/appetite: clinical studies show that heart failure patients may prefer salty food; CKD patients have reduced ability to detect salt in food. The control of salt intake by the brain is an important physiological component of sodium balance. The pathways through which the this integrates with renal function and blood pressure (BP) control are not defined. Unravelling this brain-kidney connection will help design strategies to sustain long-term reduction in salt intake in CKD.

The rare syndrome of Apparent Mineralocorticoid Excess (caused by null mutations in the gene encoding 11ß-HSD2) is used here as a paradigm of abnormal sodium homeostasis and nephropathy. Patients (and knockout mice) have pronounced salt appetite and renal dysfunction, are hypertensive and proteinuric. To resolve this complex disease, we selectively deleted 11ß-HSD2 in the central nervous system of mice, leaving renal activity unaffected. Kidney function and BP were initially normal but this small change in the brain induced a strong salt appetite. High salt intake caused hypertension and, in pilot studies, caused renal sodium retention and reduced renal perfusion. Importantly, high salt diet did not change BP or renal function in control mice.

We propose that 11ß-HSD2-expressing neurons control salt intake AND renal salt excretion. This connection is highly relevant to renal patients striving to control salt intake and BP and we are using this mouse to define the central and renal mechanisms causing salt-sensitive hypertension.