Renal regulation of sodium balance Stephen P. DiBartola, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus OH 43210

Renal handling of sodium Sodium is filtered by the glomeruli and reabsorbed by the tubules Energy for sodium transport in the kidney is required for the Na+-K+ ATPase located in the basolateral membranes of the tubular cells Na+-K+ ATPase maintains the low intracellular sodium concentration that facilitates sodium entry at the luminal membranes

Renal handling of sodium 67% of filtered load reabsorbed in proximal tubules 25% of filtered load reabsorbed in loop of Henle 5% of filtered load reabsorbed in distal convoluted tubule and connecting segment 3% of filtered load reabsorbed in collecting duct

Mechanisms for sodium reabsorption differ in different parts of the nephron

Sodium reabsorption: Early proximal tubule Luminal entry Co-transport with glucose, amino acids, Pi Na+-H+ antiporter Basolateral exit Na+-K+ ATPase Tubular fluid Cl- concentration increases

Sodium reabsorption: Late proximal tubule Luminal entry Na+-H+ antiporter in parallel with Cl--Anion- antiporter (H+-Anion- recycled) Basolateral exit Na+ actively via Na+-K+ ATPase Cl- passively via Cl- channel

Sodium reabsorption: Thin limb of Henle’s loop Thin descending limb: Passive NaCl entry into tubular lumen Thin ascending limb: Passive NaCl reabsorption

Sodium reabsorption: Thick ascending limb of Henle’s loop Luminal entry Na+-H+ antiporter Na+-K+-2Cl- cotransporter (site of action of furosemide and bumetanide) Basolateral exit Na+-K+ ATPase Tubular lumen strongly positive relative to peritubular interstitium

Sodium reabsorption: Distal convoluted tubule Luminal entry Na+-Cl- cotransporter (site of action of thiazide diuretics) Basolateral exit Na+ via Na+-K+ ATPase Cl- via Cl- channel

Sodium reabsorption: Connecting segment and collecting duct Luminal entry Passively via Na+ channel (site of action of amiloride and triamterene) Basolateral exit Na+-K+ ATPase Lumen-negative TEPD generated by Na+ movement facilitates Cl- reabsorption

Renal regulation of sodium balance Extracellular fluid volume is directly dependent on body sodium content Adequacy of body sodium content is perceived as the fullness of the circulating blood volume (“effective circulating volume”)

Sensors for control of sodium balance Low pressure mechanoreceptors (“volume” receptors) Atria Pulmonary vessels High pressure baroreceptors (“pressure” receptors) Aortic arch Carotid sinus Afferent arterioles of glomeruli

Effectors for control of sodium balance: the KIDNEY Filtration? NO: Autoregulation of GFR, tightly regulated serum Na+ concentration Reabsorption? YES: Several overlapping mechanisms insure control of Na+ balance

Control of renal sodium reabsorption Glomerulotubular balance Aldosterone Peritubular capillary factors (Starling forces) Other Catecholamines Angiotensin II Atrial natriuretic peptide “Pressure” natriuresis

Glomerulotubular balance As spontaneous (primary) fluctuations in GFR occur, absolute tubular reabsorption of filtered solutes changes in a similar direction (i.e. the fraction of the filtered load that is reabsorbed remains constant) This effect does NOT occur when a compensatory (secondary) fluctuation in GFR occurs in response to changes in sodium and water ingestion

Glomerulotubular balance: Mechanisms Spontaneous increase in GFR would increase filtered load of glucose, amino acids, and phosphate, bicarbonate Spontaneous increase in GFR would increase filtration fraction and alter peritubular Starling forces such that water and solute reabsorption in the proximal tubules would be facilitated

Aldosterone Alters renal Na+ reabsorption in response to dietary fluctuations Main stimuli for release: Angiotensin II, hyperkalemia, ACTH Main effect: Increases number of open luminal Na+ channels and activity and number of basolateral Na+-K+ ATPase pumps in principal cells of collecting ducts

Peritubular capillary factors (Starling forces) Think of the effects on P and  Increased Na+ intake: ECF expansion GFR & RPF increase proportionately (FF unchanged) Decreased Na+ intake: ECF contraction RPF decreases more than GFR (FF increased)

Peritubular capillary factors (Starling forces) Think of the effects on P &  when FF increases Increased Na+ intake: ECF expansion GFR & RPF increase proportionately (FF unchanged) Decreased Na+ intake: ECF contraction RPF decreases more than GFR (FF increased)

Catecholamines Efferent > afferent arteriolar constriction (increased FF) results in changes in peritubular Starling forces that facilitate Na+ reabsorption Direct stimulation of proximal tubular Na+ reabsorption Stimulation of renin release

Angiotensin II Efferent > afferent arteriolar constriction (increased FF) results in changes in peritubular Starling forces that facilitate Na+ reabsorption Direct stimulation of Na+-H+ antiporter in proximal tubules Stimulates aldosterone secretion from adrenal glands

Atrial natriuretic peptide Stimulus for release is atrial distension caused by volume expansion Inhibits Na+ reabsorption in some parts of the collecting duct Directly increases GFR Inhibits renin and aldosterone secretion

“Pressure” natriuresis Renal Na+ and water excretion are increased when renal arterial pressure increases without change in GFR Mechanism is intra-renal and does not require neural or endocrine input

Regulation of water balance Osmolality of ECF and serum sodium concentration are regulated by adjusting water balance Water output: Anti-diuretic hormone (vasopressin) Water intake: Thirst

Regulation of water balance Sensors Osmoreceptors in hypothalamus Effectors Anti-diuretic hormone (vasopressin) Increases permeability of cortical and medullary collecting ducts to water and medullary collectiong ducts to urea

Stimuli for ADH release Plasma hypertonicity (1 to 2% increase leads to maximal ADH release) Volume depletion (5 to 10% decrease facilitates ADH release) Other Nausea Pain Anxiety Drugs

Review of renin-angiotensin system (RAS) Synthesized by granular cells of JGA Release stimulated by decreased renal perfusion pressure, increased sympathetic tone, decreased delivery of Cl- to macula densa Release inhibited by angiotensin II Converts angiotensinogen to angiotensin I (A-I) Angiotensin II Prodcued by action of converting enzyme on A-I Arteriolar vasoconstriction throughout body Enhances renal excretion of Na+ and water