Volume Regulation and Renin Angiotensin System (RAS) 03/25/15

Describe regulation of renin secretion and the direct and indirect actions of angiotensin II.

• Retention of Na+ Renal arteriolar constriction tends to decreases GFR decreases filtered load of Na+ Direct effect to increase proximal tubular Na+ reabsorption (stimulates Na+/H+ exchange) Indirect effect (through aldosterone) to increased Na+ reabsorption by the collecting duct Net effect: conserve Na+ (and water) to support ECF volume (and cardiac output) • Vasoconstriction Direct effect on vascular smooth muscle Indirect effect: Stimulates sympathetic activity via effects on the central nervous system Net effect: increase total peripheral resistance to support systemic arterial pressure • Promote acquisition & retention of water Stimulates thirst acquire water Stimulate ADH release promotes water retention Decreases medullary blood flow Net effect: conserve and acquire water to increase ECF volume

Describe the challenges that alter sodium balance and GFR, e.g. what is glomerulotubular balance?

A constant fraction of filtered sodium is reabsorbed by the proximal tubule. When a sudden increase in GFR happens, a greater filtered load enters Bowman's space, and the plasma left behind in the glomerulus has a higher oncotic pressure. Thus, the blood in the postglomerular capillaries has a higher oncotic pressure, allowing more reabsorption to occur (stronger force favoring reabsorption). - This is called glomerulotubular balance, and lowers the effect of the increased GFR on the distal nephron. In addition, an increase in GFR can be detected by the macula densa, which can signal JG cells to constrict the afferent arteriole, thus reducing GFR again (tubuloglomerular feedback).

Very specific case of renal arterial stenosis

ACE inhibitors do not have much effect on GFR in the normal individual when given for hypertension Possibly because dilatation in Aff and Eff is nullified by the fall in blood pressure However, in renal disease where perfusion pressure is very low (eg renal artery constriction/stenosis), the constriction of the efferent arteriole is only element maintaining GFR. ACE inhibitors here would release this constriction and GFR would fall dangerously low = renal failure

Role of ANG II on GFR

ANG II is released in response to a decrease in perfusion pressure Thus GFR needs to be maintained in face of low perfusion pressure ANG II causes a constriction of efferent arteriole, reducing RBF, increasing GFR, but increasing FF (this increases reabsorption of Na in PT) However it also constricts afferent, reducing RBF and GFR Also constricts mesangial cells to reduce surface area across which to filter, this would lower GFR

List the effect of other hormones that act directly on renal tubules to alter Na+ reabsorption.

Aldosterone - Aldosterone is released in response to increases in angiotensin II, decreases in plasma Na+, and increases in plasma K+ - It increases Na+ reabsorption in the collecting duct via ENaC Catecholamines (norepinephrine and epinephrine) - Activated by sympathetic nervous system (released as neurotransmitter and into bloodstream in case of epinephrine) - Increases the reabsorption in the proximal tubule via the Na+/H+ exchanger Atrial Natriuretic Peptide - Atrial stretch due to increased ECF volume stimulates the release of ANP - It decreases the Na+ reabsorption in the collecting duct by inhibiting the ENaC Endogenous Digitalis-like Substance - Activated in response to increased ECF - Decreases Na+ reabsorption by all nephron segments by inhibiting the basolateral Na+,K+-ATPase

Cellular Actions of Aldosterone

Aldosterone permeates cells of collecting duct and binds to cytosolic receptor Steroid/Receptor complex is translocated into the nucleus Aldosterone permeates cells of collecting duct and binds to cytosolic receptor Steroid/Receptor complex is translocated into the nucleus Activates the transcription of specific mRNA These translated proteins are called AIP (aldosterone induced proteins), NKATPase, and ENaC (Epithelial Na Channel)

Explain how the following factors influence sodium excretion: glomerular filtration rate, aldosterone, changes in postglomerular (peritubular) Starling forces, atrial natriuretic peptide, sympathetic nerve stimulation, and endogenous digitalis-like substance.

Glomerular filtration rate: Sodium excretion is a factor of the filtered load minus the amount of sodium that is reabsorbed. If GFR increases, the filtered load of sodium increases; the amount of sodium excreted also increases. Aldosterone: acts on the collecting duct to increase the activity of the ENaC channel, thus increasing reabsorption of sodium (decreasing excretion). Glomerular Starling forces: increased hydrostatic pressure in the glomerulus increases GFR and thus sodium excretion. Decreases in osmotic pressure in the glomerulus also increases GFR and thus sodium excretion. Postglomerular Starling forces: decreased hydrostatic pressure in the postglomerular capillaries increases sodium reabsorption, thus reducing sodium excretion. Increased osmotic pressure in the postglomerular capillaries increases reabsorption of water (and thus sodium by solvent drag), also reducing sodium excretion. Atrial natriuretic peptide: decreases sodium reabsorption in the collecting duct by inhibiting ENaC. Thus, sodium excretion is increased. Sympathetic nerve stimulation: decreases GFR and increases sodium reabsorption in the proximal tubule. This decreases sodium excretion. Endogenous digitalis-like substance: acts to block the Na,K-ATPase, decreasing sodium reabsorption throughout the nephron. This increases sodium excretion.

Describe the role of the renin-angiotensin system in maintaining sodium balance.

The juxtaglomerular cells of the kidney release renin in response to decreases in blood pressure, fluid volume, or as a result of beta adrenergic stimulation. Renin is formed in specialized smooth muscle cells of the afferent arteriole known as granular cells (or juxtaglomerular cells). These cells directly detect blood volume and release renin when it is low. In addition, if flow decreases across the macula densa, the macula densa will signal the juxtaglomerular cells to release renin. Betaadrenergic receptor activation (stimulated via sympathetic nerves that are activated when low blood pressure is detected by baroreceptors) also stimulates the JG cells to release renin. Renin cleaves angiotensinogen to Angiotensin I. ACE converts Angiotensin I to Angiotensin II. - Direct effects: Angiotensin II acts to promote vasoconstriction by acting on vascular smooth muscle; this decreases GFR and the filtered load of sodium (more sodium retention). It acts on the proximal tubule to increase Na+ reabsorption by the Na/H exchanger. It also stimulates the thirst center in order to bring in more volume via drinking. - Indirect effects: Angiotensin II stimulates the adrenal gland to release aldosterone, which increases Na+ reabsorption in the collecting duct (via ENaC). It also stimulates the release of ADH from the posterior pituitary, which causes the collecting duct to become permeable to water (i.e. more water is reabsorbed). - All of this increases sodium and water reabsorption to increase blood volume and blood pressure.

Effect of Catecholamines (epinephrine & norepinephrine) That Acts Directly on Tubular Epithelium to Alter Na+ Reabsorption

a. Stimuli: Activation of Sympathetic Nervous System (i.e. baroreflex response to decreased arterial pressure) b. Action: Increase Na+ reabsorption by proximal tubule c. Mechanism: Activates the apical Na+/H+ exchanger

Effect of Atrial Natriuretic Peptide (ANP) That Acts Directly on Tubular Epithelium to Alter Na+ Reabsorption

a. Stimuli: Atrial stretch (as a result of increased ECF volume) b. Action: Decrease Na+ reabsorption by collecting duct c. Mechanism: Inhibits ENaC

Effect of Endogenous Digitalis-like Substance That Acts Directly on Tubular Epithelium to Alter Na+ Reabsorption

a. Stimuli: Increased ECF volume (mechanism unknown) b. Action: Decrease Na+ reabsorption by all nephron segments c. Mechanism: Direct effect to inhibit the basolateral Na+-K+-ATPase

Effect of Aldosterone That Acts Directly on Tubular Epithelium to Alter Na+ Reabsorption

a. Stimuli: Increased circulating AngII levels Decreased plasma Na+ concentration Increased plasma K+ concentration (important regulator of K+ balance) b. Action: Increase Na+ reabsorption by collecting duct c. Mechanism: Promotes Na+ entry through the apical ENaC