Abstract P237: Alterations In Renal Sodium Handling Proteins Determined By Urinary Extracellular Vesicle Analysis During Dietary Sodium Modulation And In Primary Aldosteronism

Sodium handling is altered during extremes in dietary sodium intake or in pathologic conditions such as primary aldosteronism. Urinary extracellular vesicles (uEVs) are excreted by all cell types along the nephron, are enriched for membrane proteins, and could provide insight into renal physiology in humans. We assessed uEV protein excretion of renal epithelial proteins relevant to sodium handling from 54 volunteers with pre-hypertension on high (HS, 200 mmol/d) and low (LS, 10 mmol/d) sodium diet for 5-7 days. To compare pathologic versus physiologic responses to aldosterone excess, samples were collected from 9 patients with primary aldosteronism (PA). uEVs were isolated by ultracentrifugation and trypsin digested proteins were quantified using multiple reaction monitoring mass spectrometry using isotopically labeled standards, normalized to the uEV-specific marker CD9. Wilcoxon signed rank and rank sum tests were used for within-subject and between-subject comparisons, respectively. LS diet altered uEV excretion of pendrin (4.0, expressed as fold-change vs HS), aquaporin-2 (-2.03), TRPV5 (-1.91), NCC (1.51), OSR1 (1.42; P <0.01 for all), and SGLT2 (1.20, P =0.042). In primary aldosteronism, expression of ENaC-α, ENaC-β, and ENaC-γ, NCC, SGLT2, and OSR-1 were increased to a greater extent compared to during LS diet ( P <0.05 for each), whereas AQP2 and TRPV5 were similar to HS diet ( Figure ). Expression of uEV proteins relevant to renal tubular sodium handling are dynamically altered by dietary sodium restriction and aldosterone excess. Further studies could identify patterns specific to pathologic versus physiologic aldosterone responses.

Nox4 Maintains Blood Pressure during Low Sodium Diet

The NADPH oxidase Nox4 is a hydrogen peroxide (H2O2)-producing enzyme, with the highest expression in the kidney. As the kidney is involved in volume and blood pressure control through sodium handling, we set out to determine the impact of a low sodium diet on these parameters in WT and Nox4-/- mice. Nox4 expression in the murine kidney was restricted to the proximal tubule. Nevertheless, low-sodium-induced weight loss and sodium sparing function was similar in WT and Nox4-/- mice, disputing an important function of renal Nox4 in sodium handling. In contrast, a low sodium diet resulted in a reduction in systolic blood pressure in Nox4-/- as compared to WT mice. This was associated with a selectively lower pressure to heart-rate ratio, as well as heart to body weight ratio. In general, a low sodium diet leads to activation of sympathetic tone and the renin angiotensin system, which subsequently increases peripheral resistance. Our observations suggest that the control by this system is attenuated in Nox4-/- mice, resulting in lower blood pressure in response to low sodium.

Tubulopathy meets Sherlock Holmes: biochemical fingerprinting of disorders of altered kidney tubular salt handling

Evolution moves in mysterious ways. Excretion of waste products by glomerular filtration made perfect sense when life evolved in the ocean. Yet, the associated loss of water and solutes became a problem when life moved onto land: a serious design change was needed and this occurred in the form of ever more powerful tubules that attached to the glomerulus. By reabsorbing typically more than 99% of the glomerular filtrate, the tubules not only minimise urinary losses, but, crucially, also maintain homeostasis: tubular reabsorption and secretion are adjusted so as to maintain an overall balance, in which urine volume and composition matches intake and environmental stressors. A whole orchestra of highly specialised tubular transport proteins is involved in this process and dysfunction of one or more of these results in the so-called kidney tubulopathies, characterised by specific patterns of clinical and biochemical abnormalities. In turn, recognition of these patterns helps establish a specific diagnosis and pinpoints the defective transport pathway. In this review, we will discuss these clinical and biochemical “fingerprints” of tubular disorders of salt-handling and how sodium handling affects volume homeostasis but also handling of other solutes.

Nondipping Blood Pressure: Predictive or Reactive Failure of Renal Sodium Handling?

Blood pressure follows a daily rhythm, dipping during nocturnal sleep in humans. Attenuation of this dip (nondipping) is associated with increased risk of cardiovascular disease. Renal control of sodium homeostasis is essential for long-term blood pressure control. Sodium reabsorption and excretion have rhythms that rely on predictive/circadian as well as reactive adaptations. We explore how these rhythms might contribute to blood pressure rhythm in health and disease.