Maintaining Balance under Pressure: The role of proximal tubule sodium transport in regulation of extracellular fluid volume and blood pressure

This presentation was given by Alicia McDonough from the Department of Cell and Neurobiology of the Keck School of Medicine of USC in California, USA. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 7: Novel Mechanisms in Salt and Water Homeostasis.


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 Presentation Abstract: 

Hypertension is the leading cause of stroke and cardiovascular diseases, affecting 30% of the adult population.  Excessive Na+ input can acutely raise effective circulating volume (ECV) and blood pressure (BP) but normally the kidneys excrete enough Na+ and volume to normalize BP, a response termed “pressure natriuresis.”  The molecular mechanisms responsible for the interdependence of BP and ECV converge on regulation of renal proximal tubule (PT) Na+ transporters.  PT reabsorbs 2/3 of the filtered Na+ and volume at baseline.  This fraction decreases when BP or ECV increase, facilitated by local 20-HETE, dopamine and AT2R mediated signalling; conversely, the fraction increases during AngII or SNS stimulation.  These variables regulate the Na+/H+ exchanger isoform 3 (NHE3) and the Na+-phosphate co-transporter (NaPi2).

Natriuretic stimuli, e.g. hypertension, provoke the dynamic redistribution of NHE3 and NaPi2 along with associated regulators, molecular motors and cytoskeletal associated proteins to the base of the microvilli.  The lipid raft associated NHE3 remains at the base where activity is suppressed and the non-raft associated NaPi2 is endocytosed culminating in decreased Na+ reabsorption and increased volume flow out of the PT, thus, contributing to acute pressure natriuresis.

Infusion of the anti-natriuretic AngII into rodents initially (before hypertension develops) increases the abundance of PT NHE3, as well as abundance and activation of distal nephron transporters.  During longer AngII infusion hypertension develops and distal transporters remain stimulated while abundance of PT NHE3 and medullary NKCC2 significantly decrease, evidence for activation of a chronic pressure-natriuretic response that opposes the actions of AngII stimulation in the pre-macula densa nephron.

During chronic AngII hypertension, CD8+ cells infiltrate the kidneys and produce interferon gamma and interleukin 17A (Harrison lab, Vanderbilt).  IFN-?-/- and IL-17A-/- mice exhibit similarly blunted hypertensive responses to AngII and similarly amplified natriuretic responses to a saline challenge vs. WT mice.  Interestingly, NHE3 and NaPi2 (as well as myosin VI) are depressed from baseline far more in the mice lacking either (IFN-? or IL-17A) cytokine compared to WT mice demonstrating that: the pressure natriuresis potential is blunted in WT mice during AngII infusion, and that cytokines produced during AngII infusion contribute to the blunting by preventing, (directly or indirectly), the suppression of NHE3 and NaPi2 in response to high BP.  Distal transporter responses to AngII were blunted in the IFN-?-/- but not in IL-17A-/- compared to WT, pointing to the overriding impact of proximal nephron in the natriuresis and BP set point.

Pre-menopausal females exhibit lower BP than males and their pressure natriuresis response is set to lower BP.  In female rodents (vs. males) NHE3 is redistributed to the base of the microvilli, NHE3pS552, a marker for inactive NHE3, is higher, while NaPi2 and myosin VI (the motor that drives the transporters) are lower.  Physiologically, females exhibit significantly higher rates of endogenous Li+ clearance, and excrete a saline volume challenge more rapidly than males, both providing evidence for lower fractional PT reabsorption in females.  

Determining how and why pressure natriuresis is blunted during hypertension:, e,g, by local AngII, by cytokines, and in males, will provide a new way of thinking about how to control blood pressure and motivate strategies to decrease proximal nephron sodium transporter activation.

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