Salt Sensitivity and Tubular Mechanisms of Pressure Natriuresis: A Mathematical Modeling Analysis
Authors: Hallow Melissa , Helmlinger Gabriel , Gebremichael Yeshitilla 
Published: November 2023

Individuals whose blood pressure is sensitive to changes in salt intake are at increasesd risk for developing hypertension and cardiovascular disease. This salt‐sensitivity results from impairment in the kidney's ability to adapt sodium excretion to changes in sodium intake, and Arthur Guyton demonstrated that shifting of the pressure‐natriuresis curve results in salt‐sensitivity. However, the underlying mechanisms responsible for the pressure‐natriuresis phenomenon continue to be debated, and the processes responsible for impairment in this mechanism are not well understood. Renal perfusion pressure (RPP) is thought to drive adaptations in tubular sodium reabsorption through changes in renal interstitial hydrostatic pressure (RIHP). Yet we still do not fully understand how RPP is transmitted to RIHP, how it is sensed by the tubules, the contribution of each tubular segment to pressure‐natriuresis, or the impact of impairment in each step in this tubular pressure‐natriuresis process.In this study, we used a mathematical model of renal filtration and blood volume regulation, including intrinsic and neurohormonal feedback mechanisms, to explore the physiologic processes that allow the kidney to maintain sodium balance. We first demonstrated, as has been shown experimentally, that a tubular pressure‐natriuresis mechanism, wherein tubular sodium reabsorption adapts to changes in RIHP, can account for salt resistance, and that lack of this mechanism results in salt‐sensitivity. We then explored the role of each tubular segment in contributing to pressure‐natriuresis, and found that the collecting duct (CD) response to RIHP is critical for robust salt resistance. Without changes in CD reabsorption, upstream changes in proximal and loop of Henle sodium reabsorption alone would not be able to accommodate more than a 4‐fold change in salt intake.We also explored the impact of alterations in each step in the pressure‐natriuresis process, including factors that affect transmission of RPP to the post‐glomerular capillaries and then to the interstitium, as well factors that affect the sensitivity of the tubules to changes in RIHP. We found that mechanisms that reduce the ability of the collecting duct to sense and respond to RIHP resulted in increased salt‐sensitivity, and permitted development of hypertension when accompanied by certain other factors (e.g. increased aldosterone or decreased glomerular ultrafiltration coefficient). On the other hand, pathophysiologic factors that reduced transmission of arterial pressure to the peritubular/vasa recta capillaries (e.g. angiotensin‐driven efferent constriction) or that reduced the transmission of peritubular/vasa recta pressure to RIHP (e.g. loss of peritubular capillaries) resulted in salt‐resistant hypertension. In fact, our simulations suggest that a strong tubular pressure‐natriuresis effect sensitized the blood pressure response to angiotensin, while a weak pressure‐natriuresis effect minimized the response to angiotensin. This may help explain why African Americans, who are often salt‐sensitive, also tend to be less responsive to therapies targeting the renin angiotensin system.Support or Funding InformationAstrazeneca Pharmaceuticals