Chronically elevated blood pressure (BP), or hypertension, is a major cause of preventable mortality worldwide (1). Despite application of various BP-lowering strategies, many patients do not respond with an effective lowering of BP, in line with current guidelines (1). Hence, there remains a need to define molecular mechanisms underpinning hypertension with an aim to develop and progress novel therapeutic strategies.

Diet has a strong influence on BP. Sustained high dietary Na+ consumption is associated with increased BP, with epidemiological and clinical reports presenting a positive, independent linear relationship between 24-hour Na+ excretion and BP (2-4). The effects of dietary potassium (K+) on BP are more controversial. Globally, dietary K+ intake is 1.5- to 2-fold lower than recommended (2-4). Increasing dietary K+ to recommended intake can reduce BP in hypertensive patients (5, 6). Conversely, nonhypertensive subjects kept on a constant Na+ diet demonstrate an average systolic BP (SBP) increase of 10 mmHg when subjected to dietary K+ depletion (7). Furthermore, the Dietary Approaches to Stop Hypertension (DASH) regime of dietary Na+ restriction alongside increased K+ intake causes significant reductions in BP (8), and urinary K+ excretion negatively correlates with BP (4, 9-11). Notably, a recent study demonstrated that, in older patients with hypertension, substituting 25% of dietary NaCl intake with KCl lowered SBP by ~3.5 mmHg and significantly reduced the rates of major cardiovascular events (12). Whether this is attributable to the higher K+ intake, lower Na+ intake, or a combination is unclear. Contrasting these studies, urinary K+ excretion ≥ 1 g/day, or a decrease in the urinary Na+/K+ ratio, was not associated with lower SBP in a reanalysis of the DASH trial data set obtained during the initial period where participants consumed their regular diet (13). Furthermore, a “U-shaped” association between K+ intake and BP was uncovered in a meta-analysis of randomized-controlled trials (duration ≥4 weeks), with SBP increasing when dietary intake was under 30 mmol/day or over 80 mmol/day (14).

The kidney is essential for K+ homeostasis. Almost all filtered K+ is reabsorbed in proximal segments, whereas K+ secretion in the distal segments matches urinary K+ excretion with dietary K+ intake. The activity of the thiazide-sensitive sodium-chloride-cotransporter (NCC) in the distal convoluted tubule (DCT) is important for controlling the delivery of Na+ to the downstream K+ secreting segment: the aldosterone-sensitive distal nephron (ASDN), where K+ secretion by the renal outer medullary K+ channel (ROMK) channel is electrochemically coupled to Na+ reabsorption via the epithelial Na+ channel ENaC (15). Aldosterone-regulated flow-dependent K+ secretion can also occur via big-K+ channels (“maxi-K” channels) (16, 17). The importance of Na+ delivery for K+ secretion is highlighted by disorders of Na+ reabsorption in the DCT. Urinary K+ wasting and hypokalemia develops in patients with Gitelman syndrome, as loss of NCC function causes excessive Na+ delivery to the ASDN. In contrast, urinary K+ retention and hyperkalemia are hallmarks of patients with pseudohypoaldosteronism type II (PHAII) who have hyperactivation of NCC (18, 19).

ENaC and NCC abundance and/or activity are altered by dietary K+. ENaC expression and cleavage (indicating higher activity) increase with high dietary K+ (20, 21) and decrease with K+ restriction (22). Conversely, NCC abundance and phosphorylation (indicating higher activity) often increase when dietary K+ intake is restricted (20, 22-24) but generally decrease subsequent to high dietary K+ (20, 24-26). The effects on NCC may be dependent on the period of dietary K+ intervention or the anion accompanying dietary K+ (27-29).

In an attempt to address the variable BP differences observed in humans and mice after K+ supplementation, and to better align the period of dietary intervention in mice with human studies, here we (a) determined if short-term (4 days) or chronic (21 days) K+ supplementation to mice alters BP; (b) assessed if any effects of chronic K+ supplementation on BP are dependent on the accompanying anion or the Na+ intake; and (c) determined if specific molecular alterations in the kidney underlie BP differences. Our results show that a K+-free diet increases BP in an NCC-dependent manner — an effect augmented by a high NaCl diet. Independent of the Na+ intake or accompanying anion, chronic K+ supplementation also increases BP, whereas short-term high KCl (+KCl) feeding reduces BP. These differential effects on BP occur despite a reduction in NCC abundance and phosphorylation under both dietary K+ conditions. The chronic feeding effects on BP may be driven by enhanced ENaC activity, but kidney damage may also play a role.