Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na⁺/H⁺ exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na⁺/Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na⁺/Cl⁻ cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na⁺ channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K⁺ concentration. A K⁺-rich meal increased the urinary K⁺ concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K⁺ secretion and set plasma K⁺ at a lower level.

Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration, and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically interferon-γ (IFN-γ) and interleukin-17A (IL-17A), to sodium transporter regulation in the kidney during angiotensin-II (Ang-II) hypertension. C57BL/6J (wild-type) mice responded to Ang-II infusion (490 ng/kg per minute, 2 weeks) with a rise in blood pressure (170 mm Hg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ ^−/− ) or IL-17A (IL-17A ^−/− ) exhibited a blunted rise in blood pressure (<150 mm Hg), and both the genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, Ang-II infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, and Ste20/SPS-1–related proline-alanine–rich kinase, in both the wild-type and the IL-17A ^−/− but not in IFN-γ ^−/− mice; epithelial Na channel abundance increased similarly in all the 3 genotypes. In the proximal nephron, Ang-II infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A ^−/− and IFN-γ ^−/− , but not in wild-type; the Na-phosphate cotransporter decreased in all the 3 genotypes. Our results suggest that during Ang-II hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.

One-hundred years ago, Starling articulated the interdependence of renal control of circulating blood volume and effective cardiac performance. During the past 25 years, the molecular mechanisms responsible for the interdependence of blood pressure (BP), extracellular fluid volume (ECFV), the renin-angiotensin system (RAS), and sympathetic nervous system (SNS) have begun to be revealed. These variables all converge on regulation of renal proximal tubule (PT) sodium transport. The PT reabsorbs two-thirds of the filtered Na⁺and volume at baseline. This fraction is decreased when BP or perfusion pressure is increased, during a high-salt diet (elevated ECFV), and during inhibition of the production of ANG II; conversely, this fraction is increased by ANG II, SNS activation, and a low-salt diet. These variables all regulate the distribution of the Na⁺/H⁺exchanger isoform 3 (NHE3) and the Na⁺-phosphate cotransporter (NaPi2), along the apical microvilli of the PT. Natriuretic stimuli provoke the dynamic redistribution of these transporters along with associated regulators, molecular motors, and cytoskeleton-associated proteins to the base of the microvilli. The lipid raft-associated NHE3 remains at the base, and the nonraft-associated NaPi2 is endocytosed, culminating in decreased Na⁺transport and increased PT flow rate. Antinatriuretic stimuli return the same transporters and regulators to the body of the microvilli associated with an increase in transport activity and decrease in PT flow rate. In summary, ECFV and BP homeostasis are, at least in part, maintained by continuous and acute redistribution of transporter complexes up and down the PT microvilli, which affect regulation of PT sodium reabsorption in response to fluctuations in ECFV, BP, SNS, and RAS.

Dietary potassium loading results in rapid kaliuresis, natriuresis, and diuresis associated with reduced phosphorylation (p) of the distal tubule Na⁺-Cl⁻ cotransporter (NCC). Decreased NCC-p inhibits NCC-mediated Na⁺ reabsorption and shifts Na⁺ downstream for reabsorption by epithelial Na⁺ channels (ENaC), which can drive K⁺ secretion. Whether the signal is initiated by ingesting potassium or a rise in plasma K⁺ concentration ([K⁺]) is not understood. We tested the hypothesis, in male rats, that an increase in plasma [K⁺] is sufficient to reduce NCC-p and drive kaliuresis. After an overnight fast, a single 3-h 2% potassium (2%K) containing meal increased plasma [K⁺] from 4.0 ± 0.1 to 5.2 ± 0.2 mM; increased urinary K⁺, Na⁺, and volume excretion; decreased NCC-p by 60%; and marginally reduced cortical Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) phosphorylation 25% ( P = 0.055). When plasma [K⁺] was increased by tail vein infusion of KCl to 5.5 ± 0.1 mM over 3 h, significant kaliuresis and natriuresis ensued, NCC-p decreased by 60%, and STE20/SPS1-related proline alanine-rich kinase (SPAK) phosphorylation was marginally reduced 35% ( P = 0.052). The following were unchanged at 3 h by either the potassium-rich meal or KCl infusion: Na⁺/H⁺ exchanger 3 (NHE3), NHE3-p, NKCC, ENaC subunits, and renal outer medullary K⁺ channel. In summary, raising plasma [K⁺] by intravenous infusion to a level equivalent to that observed after a single potassium-rich meal triggers renal kaliuretic and natriuretic responses, independent of K⁺ ingestion, likely driven by decreased NCC-p and activity sufficient to shift sodium reabsorption downstream to where Na⁺ reabsorption and flow drive K⁺ secretion.

The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K⁺], there is evidence for a feedforward mechanism: Dietary K⁺ intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K⁺ excretion. This pathway may explain renal and extrarenal responses to altered K⁺ intake that occur independently of changes in ECF [K⁺]. Mechanisms for conserving ECF K⁺ during fasting or K⁺ deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K⁺ channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K⁺ uptake. How these mechanisms are triggered by K⁺ deprivation remains unclear. Cellular AMP kinase–dependent protein kinase activity provokes the acute transfer of K⁺ from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K⁺ diet for the cardiovascular system.

Potassium homeostasis has a very high priority because of its importance for membrane potential. Although extracellular K⁺is only 2% of total body K⁺, our physiology was evolutionarily tuned for a high-K⁺, low-Na⁺diet. We review how multiple systems interface to accomplish fine K⁺balance and the consequences for health and disease.