Pressure natriuresis and the renal control of arterial blood pressure

Abstract

The regulation of extracellular fluid volume by renal sodium excretion lies at the centre of blood pressure homeostasis. Renal perfusion pressure can directly regulate sodium reabsorption in the proximal tubule. This acute pressure natriuresis response is a uniquely powerful means of stabilizing long-term blood pressure around a set point. By logical extension, deviation from the set point can only be sustained if the pressure natriuresis mechanism is impaired, suggesting that hypertension is caused or sustained by a defect in the relationship between renal perfusion pressure and sodium excretion. Here we describe the role of pressure natriuresis in blood pressure control and outline the cascade of biophysical and paracrine events in the renal medulla that integrate the vascular and tubular response to altered perfusion pressure. Pressure natriuresis is impaired in hypertension and mechanistic insight into dysfunction comes from genetic analysis of blood pressure disorders. Transplantation studies in rats show that blood pressure is determined by the genotype of the kidney and Mendelian hypertension indicates that the distal nephron influences the overall natriuretic efficiency. These approaches and the outcomes of genome-wide-association studies broaden our view of blood pressure control, suggesting that renal sympathetic nerve activity and local inflammation can impair pressure natriuresis to cause hypertension. Understanding how these systems interact is necessary to tackle the global burden of hypertension.

Figure 1. The relationship between blood pressure and sodium excretion

A, the acute pressure natriuresis response can be induced experimentally by imposing serial pressure ramps upon the kidney using arterial constriction. B, the relationship between blood pressure, taken as a surrogate of renal perfusion pressure, and sodium excretion is flattened in experimental hypertension. C, a rise in blood flow through the vasa recta stimulates local production of paracrine agents such as nitric oxide (NO) and ATP, which can inhibit tubular sodium reabsorption at multiple sites. The rise in renal interstitial hydrostatic pressure (RHIP) reduces sodium reabsorption in the proximal tubule.

Figure 2. Simplified diagram of the proposed cycle of inflammation produced by the adaptive immune response in hypertension

Stimuli such as angiotensin II (AngII), aldosterone or mechanical stress caused by high blood pressure cause the production of reactive oxygen species (ROS) and damage to renal and vascular tissues leading to the shedding of neoantigens. ROS also promotes the release of chemokines and adhesion molecules from damaged tissues. Neoantigens are then presented by antigen presenting cells (APCs), to T-cells within the thymus, which egress towards the sites of chemokine and adhesion molecule signalling where they proliferate and accumulate. The kidney injury, vasoconstriction and increase in sympathetic nervous system (SNS) outflow caused by the inflammatory milieu perpetuates the hypertension and creates a cycle of injury and increasing blood pressure. NOS, nitric oxide synthase.

Figure 3. Efferent and afferent pathways of the renal sympathetic nervous

Efferent preganglionic neurons originate from medullary centres such as rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS), where afferent inputs from end-organs (including the kidney) and baroreceptors are integrated. Post-ganglionic efferents synapsing at coeliac, supramesenteric and inferior mesenteric ganglia, innervate the renal tubules, juxtaglomerular apparatus (JG cells) and afferent and efferent arterioles. An increase in efferent activity evokes renin release, antinatuiresis and renovascular resistance. Renin release will stimulate the renin–angiotensin–aldosterone cascade, thus increasing renal tubular reabsorption of sodium but angiotensin II aided by circulating aldosterone can also have central nervous system effects (Blaustein et al. ; Biancardi et al. 2014). Inputs to the afferent sensory neurons of the kidney are relayed through the dorsal root ganglia (DRG) to higher brain centres such as the paraventricular nucleus (PVN), where they are integrated and the appropriate efferent output generated. For simplicity the renal efferent and afferent neurons are drawn separately, but note that the renal nerve is a compound nerve. The asterisk indicates regions of the sympathetic nervous system that have been manipulated for hypertension treatment (for a comprehensive review of renal sympathetic anatomy, see DiBona & Kopp, ; Johns, 2014).