HDCN Abstract:  ASN Annual Meeting 2020 -- Digital Meeting  

Grimm PR, Little R, Fenton RA, et al.

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

ASN Annual Meeting 2020 -- Digital Meeting
J Am Soc Nephrol (Oct) 31:40A 2020

BACKGROUND

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 is equally important. A ‘renal K switch’ that turns on the thiazide-sensitive NaCl cotransporter (NCC) in response to low dietary K intake and off in response to high K intake has been implicated. Here we test this idea in genetically engineered mice (CA- SPAK) in which the K switch is 'locked on.'

METHODS

Kinase- activating mutations were introduced in SPAK. Expression of the constitutively active (CA) SPAK mutant was limited to the early DCT and results in NCC hyperactivation. BP responses to small changes in plasma [K+] (P[K]) in CA-SPAK were compared to control mice. Dietary K content was varied over 4 days to titrate P[K] over a narrow 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 treatment, the BP response to hydrochlorothiazide (HCTZ) was measured to assess the contribution of NCC to BP.

RESULTS

BP decreased by ~10 mmHg when P[K] increased from 3.7 to 5.1 mM in control mice, coincident with the 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, supporting the idea that low K-dependent activation of NCC exacerbates the effects of Na. Studies in CA-SPAK mice reveal a causal relationship between switch activation and BP responses to Na and K. 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 K switch prevents the anti-hypertensive effects of HK. No sex differences were found.

CONCLUSION

In summary, low K consumption, common in modern diets, presses the switch pathway to turn on to conserve K at the expense of increasing Na retention, even in the face of high dietary Na, and this elevates BP. Thus, switch activation can drive salt-sensitive hypertension.

c Copyright 2020 -2021 American Society of Nephrology. Reproduced with permission.
All ASN abstracts from the 2020 Annual Meeting are available at this link and also are archived in .pdf form at ASN-Online.org

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