Periodic Reporting for period 1 - HyperK (Differential effects of dietary potassium intake on blood pressure)
Période du rapport: 2023-10-01 au 2025-09-30
As the main risk factor for the onset of cardiovascular disease, hypertension is a major contributor to premature death and disability. High salt in the diet is often considered a primary culprit for hypertension, but growing evidence indicates that increasing potassium in the diet may lower blood pressure (BP). However, dietary, observational or potassium intervention studies in animals or humans indicate that higher potassium intake is not always beneficial for BP. Reducing and maintaining a lower BP based on dietary intervention requires understanding of the long term and/or accumulated effects of the intervention and the underlying molecular basis. This project aims to increase our understanding of these different effects of dietary potassium on BP by examining the regulation mechanisms at play in the kidney.
The main objectives are to:
1) Determine the optimum dietary potassium intake that reduces and sustains a lower BP;
2) Identify factors in the kidney that drive potassium sensitivity of BP;
3) Assess if sustained high dietary potassium intake changes vascular function;
4) Investigate the molecular basis of any vascular remodeling that promotes, or is consequential, to increased BP during prolonged high dietary potassium intake.
Current pharmaceutical approaches for the management of high BP are quite effective, but adequate long-term management or responses are difficult to achieve: cardiovascular risk is nearly double in treated hypertension subjects than in individuals with normal blood pressure. This observation makes it necessary to study basic physiological questions to provide new insights into BP control. A major outcome of this research is to define if BP can be reduced long-term by manipulating dietary potassium intake. While specific drugs (that antagonize the renin-angiotensin aldosterone system) have transformed cardiovascular care, their usefulness is often limited by hyperkalemia (high potassium in the blood), which carries a significantly increased risk of mortality. New drugs to address this limitation act indirectly and have not proven popular. My studies may identify new targets in the kidney or vasculature that could be pharmaceutically exploited to manipulate BP without these limitations.
The main objectives are to:
1) Determine the optimum dietary potassium intake that reduces and sustains a lower BP;
2) Identify factors in the kidney that drive potassium sensitivity of BP;
3) Assess if sustained high dietary potassium intake changes vascular function;
4) Investigate the molecular basis of any vascular remodeling that promotes, or is consequential, to increased BP during prolonged high dietary potassium intake.
Current pharmaceutical approaches for the management of high BP are quite effective, but adequate long-term management or responses are difficult to achieve: cardiovascular risk is nearly double in treated hypertension subjects than in individuals with normal blood pressure. This observation makes it necessary to study basic physiological questions to provide new insights into BP control. A major outcome of this research is to define if BP can be reduced long-term by manipulating dietary potassium intake. While specific drugs (that antagonize the renin-angiotensin aldosterone system) have transformed cardiovascular care, their usefulness is often limited by hyperkalemia (high potassium in the blood), which carries a significantly increased risk of mortality. New drugs to address this limitation act indirectly and have not proven popular. My studies may identify new targets in the kidney or vasculature that could be pharmaceutically exploited to manipulate BP without these limitations.
First, we examined in male mice if an optimal BP-lowering potassium intake window exists and the molecular basis of potassium-driven increases in BP.
For that, telemetric BP recordings are performed in mice, and in parallel physiological measurements such as urine and blood potassium content are taken. The mice first received diets with normal (0.74%) salt content and progressively increasing potassium content (0.75% to 5%, as KCl) for 5 days each.
None of the diets examined reduced BP despite lowering the activity of the sodium-chloride-cotransporter NCC; above 1.75% potassium intake, systolic BP (SBP) is raised, concurrent with higher aldosterone and sodium channel (ENaC) activity. This was in contradiction with our initial hypothesis, which was the identification of an increased potassium intake that lowers BP long-term.
Then, mice received either control (0.75%) or high (2%) potassium on a high salt (4%) diet. On this high salt diet, potassium-driven increases in ENaC and SBP are absent and high NaCl does not increase SBP.
The main results show that, in mice:
- On normal dietary salt intake, increasing dietary potassium raised plasma potassium, aldosterone, and systolic BP.
- Higher potassium intake reduced activity of sodium-chloride-cotransporter NCC, increased sodium channel ENaC.
- Higher potassium intake did not cause changes in kidney injury markers, indicating that injury is unlikely to be a short-term reason for higher BP.
- A moderate increase in potassium intake prevented BP increase due to high salt
- On normal salt intake, there was a dose-response relationship between aldosterone levels and BP.
- High salt diet lowered NCC and ENaC abundances, even if potassium was high
For that, telemetric BP recordings are performed in mice, and in parallel physiological measurements such as urine and blood potassium content are taken. The mice first received diets with normal (0.74%) salt content and progressively increasing potassium content (0.75% to 5%, as KCl) for 5 days each.
None of the diets examined reduced BP despite lowering the activity of the sodium-chloride-cotransporter NCC; above 1.75% potassium intake, systolic BP (SBP) is raised, concurrent with higher aldosterone and sodium channel (ENaC) activity. This was in contradiction with our initial hypothesis, which was the identification of an increased potassium intake that lowers BP long-term.
Then, mice received either control (0.75%) or high (2%) potassium on a high salt (4%) diet. On this high salt diet, potassium-driven increases in ENaC and SBP are absent and high NaCl does not increase SBP.
The main results show that, in mice:
- On normal dietary salt intake, increasing dietary potassium raised plasma potassium, aldosterone, and systolic BP.
- Higher potassium intake reduced activity of sodium-chloride-cotransporter NCC, increased sodium channel ENaC.
- Higher potassium intake did not cause changes in kidney injury markers, indicating that injury is unlikely to be a short-term reason for higher BP.
- A moderate increase in potassium intake prevented BP increase due to high salt
- On normal salt intake, there was a dose-response relationship between aldosterone levels and BP.
- High salt diet lowered NCC and ENaC abundances, even if potassium was high
The main results can be summarised as such: The higher BP subsequent to excess potassium intake is aldosterone and ENaC-dependent, and increased dietary potassium is beneficial when salt intake is high.
Our original hypothesis was that a moderate increase in dietary potassium could reduce and sustain lower BP through inhibition of NCC activity. However, we found that at the 4 to 5-day timepoint where BP was recorded, none of the dietary intakes had the capacity to reduce BP, and therefore we did not extend the dietary feeding period for longer.
Explanation for this response are that: 1) the “window” of intakes we used were already too large and masked any beneficial effects. 2) In mice, the standard diets consumed and here used as control have already an almost optimal potassium content for low BP.
Therefore, for future studies, we suggest to focus on feeding mice a potassium-deficient diet with variable salt intake, to mimic the general population of humans, followed by assessment of BP during very small increments in dietary K+ intake. Such interventional studies in mice would confirm that a narrow BP-lowering “potassium window” exists, that could be translatable to humans.
Our original hypothesis was that a moderate increase in dietary potassium could reduce and sustain lower BP through inhibition of NCC activity. However, we found that at the 4 to 5-day timepoint where BP was recorded, none of the dietary intakes had the capacity to reduce BP, and therefore we did not extend the dietary feeding period for longer.
Explanation for this response are that: 1) the “window” of intakes we used were already too large and masked any beneficial effects. 2) In mice, the standard diets consumed and here used as control have already an almost optimal potassium content for low BP.
Therefore, for future studies, we suggest to focus on feeding mice a potassium-deficient diet with variable salt intake, to mimic the general population of humans, followed by assessment of BP during very small increments in dietary K+ intake. Such interventional studies in mice would confirm that a narrow BP-lowering “potassium window” exists, that could be translatable to humans.