A Renal Potassium‐Switch Prioritizes Dietary Potassium Over Sodium, Driving Salt‐Sensitive Hypertension

Reducing dietary salt (NaCl) is well appreciated to lower blood pressure (BP), but a growing body of evidence indicates that increasing dietary potassium (K + ) intake plays an equally important role. A ‘renal potassium switch’ that turns on the thiazide‐sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) in response to low dietary potassium intake and off in response to high potassium intake has been implicated. Here we test the idea in genetically engineered mice, containing a DCT1‐specific, conditionally active SPAK (CA‐SPAK mice) which phospho‐activates NCC, and locks the switch “on.” BP responses to small, physiologic changes in plasma [K + ] (P[K+]) in CA‐SPAK mice were compared to control mice. Dietary potassium content was varied to acutely titrate P[K+] over a physiologic range (3.7mM (LK), 4.4mM (MK), and 5.1mM (HK)). Blood pressure was monitored by telemetry at each P[K+] level in mice consuming control or high salt diet (HNa). At the end of each dietary treatment, the BP response to hydrochlorothiazide (HCTZ) was measured to assess the contribution of NCC to BP. BP decreased by ~10 mmHg when P[K+] increased from 3.7 to 5.1 mM in control mice, coincident with inactivation of NCC. When the switch was on (LK and MK groups), HNa significantly elevated BP but had no effect when the switch was inactivated by HK. HCTZ significantly reduced BP in the LK/HNa and MK/HNa groups but had no effect on BP in the HK/HNa group, further supporting the idea that low potassium‐dependent activation NCC exacerbates the effects of sodium. Studies in CA‐SPAK mice reveal a causal relationship between switch activation and BP responses to sodium and potassium. In contrast to control mice, increasing P[K+] in CA‐SPAK mice had no effect on BP under control salt conditions and failed to blunt the significant hypertensive effects of HNa. HCTZ significantly decreased BP in all CA‐SPAK groups to near control levels, consistent with NCC‐driven salt reabsorption. Thus, locking on the potassium switch prevents the anti‐hypertensive effects of HK. No sex differences were found. In summary, low K + consumption, common in modern diets, presses the switch pathway to turn on to conserve K + at the expense of increasing sodium retention, even in the face of high dietary sodium, and this elevates BP. Thus, switch activation can drive salt‐sensitive hypertension. Support or Funding Information NIH