1. Lecture 5 Regulation of Sodium and Water Excretion ….. essentially same as….. Regulating Plasma Volume and Osmolarity

2. Kidneys excrete salt and water Since the amounts of salt and water in body define blood volume & osmolarity, Kidney’s control blood volume and body fluid osmolarity.

3. Renal Role in Blood Pressure Regulation ► Short Term BP Control: seconds/minutes classic baroreceptor reflex sympathetic output changes vascular resistance (MRP) ► Medium Term BP Control: minutes/hours renin release renin promotes angiotensin II formation circulating angiotensin II changes vascular resistance (MRP) ► Long Term BP Control: hours/days changes in total body salt & H 2 0 changes blood volume (MRP) The Kidney’s Role: 1) renin release (min/hrs) 2) controlling blood volume (hrs/days) Blood volume changes when H 2 0 moves in or out of the plasma. H 2 0 always moves down osmotic gradients. CONCEPT: CONCEPT: If you control Na +, then you control blood volume. Most abundant osmotically active particle in plasma is Na +. Control of Na = control of H 2 0 movement = Control of volume

4. Regulation of Na+ & H 2 0 Balance Natriuresis Natriuresis is the process of excretion of sodium in urine via action of the kidneys Diuresis Diuresis is excretion of a large volume of urine Definitions: Natriuresis resulting from an increase in renal arterial pressure is called pressure natriuresis Likewise, a diuresis resulting from in renal arterial pressure is called pressure diuresis

5. Regulation of Na + & H 2 0 Balance First a Conceptual Overview Parallel Bulk Handling Differential Hormonal Fine-Tuning Pressure Natriuresis Aldosterone ….. Na ADH ….. H 2 0

6. Regulation of Na + Balance Pressure Natriuresis More IN More OUT Some Murky Mechanism Details: Some evidence that increased BP some how down regulates Na reabsorption from the proximal tubule Higher hydrostatic pressure in peritubular capillaries reduces reabsorption from the proximal tubule. Pressure Natriuresis: 1) it is driven by simple hemodynamics 2) it is largely a proximal nephron phenomenon 3) it does not involve any sensors or circulating factors Simply Hemodynamics : More IN = More OUT (  GFR →  Na + &H 2 O excreation) No independent treatment of Na + & H 2 0 Good for simple bulk volume control Note: Note: Pressure natriuresis can help in controlling blood volume (and BP) but it is not very useful for independetly controlling Na + and H 2 O balance

7. Regulation of Na + Balance Why does the body need to regulate Na + balance independently of H 2 O ? Independent regulation of Na+ balance allows the body to compensate for the reality that Na + and H 2 O ingestion are both highly variable and often do not occur simultaneously High Na + load, low H 2 O → Body has hormonal mechanisms to modulate Na + and H 2 O balance independetly → Body has hormonal mechanisms to modulate Na + and H 2 O balance independetly High H 2 O load, low Na +

8. Regulation of Na + in Distal Nephron Aldosterone: Most important “H 2 0-independent” controller of Na + reabsorption & Na + balance → Steroid hormone produced by adrenal cortex → Acts on principle cells of the collecting duct → Circulating Angiotensin II stimulates its release ► Aldosteron action in CD is essentially “fine-tuning” Na + output ► Only 2% of filtered Na + under aldosterone regulaton Differential Hormonal Fine-Tuning Collecting Duct Total Na + filtered per day = GFRxPNa = 180L/dayX145mmoles/L = 26,100mmoles/day Thus aldosterone controls 522 mmoles/day This represent ~ 30grams of table salt (NaCl)

9. …  BP triggers baroreceptor response …  BP & sympathetic inputs trigger renin release from granular cells … renin enters circulation and leads to increased angiotensin II levels … angiotensin II triggers aldosterone release from adrenal cortex … aldosterone stimulates Na reabsorption from collecting duct … the retained Na leads to increased blood volume which raises BP Note: Aldosterone is not the only hormone that regulates the body’s Na + balance. Renin-angiotensin-aldosterone control system response to decrease in arterial BP

10. Atrial Natriuretic Peptide Atrial NatriureticPeptide Atrial NatriureticPeptide - promotes Na + excretion(ANP) → released from heart when atria stretch due to high blood volume (  BP) → vasodilates afferent arteriole increasing GFR → inhibits Na + reabsorption in from collecting duct → inhibits renin-angiotensin- aldosterone system ANP control system response to a increase in arterial BP

11. Regulation of H 2 0 Balance Key circulating hormone that regulate distal H 2 O reabsorption in the collecting duct Antidiuretic Hormone (ADH) Antidiuretic Hormone (ADH) sometimes called vasopressin Collecting Duct ADH : Peptide hormone Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly Stored in vesicles at the posterior pituitary Remember?! How ADH alters the H 2 O permeability of the collecting duct? ADH ADH - promotes insertion aquaporins, the apical membrane become H 2 O permeable and thus H 2 O is reabsorbed (i.e less excreted)

12. Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release

13. Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Baroreceptors

14. Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Osmoreceptors The cells that release ADH integrate the 2 input signals. “2 heads are better than 1”

16. Input Signals that Control ADH Release 1) cardiovascular baroreceptors  BP  less baroreceptor firing   ADH release  BP  more baroreceptor firing   ADH release 2) hypothalamic osmoreceptors  plasma osmolarity   ADH release  plasma osmolarity   ADH release Generally, osmolarity usually dominates unless there are very large changes in volume. Certain other brain level inputs can alter short-term ADH release (fear, pain, alcohol). Diabetes insipidus is due to abnormal ADH regulation. Origin could be brain problem or bad renal ADH receptors.

18. Free Water Clearance (C H20 ) means to access renal H 2 0 handling, not the usual clearance calculation The C H 2 0 determination considers urine as having 2 parts: Urine Volume solute-free H 2 0 H 2 0 with solute  Can be calculate as Osmolar Clearance C OSM = U OSM · V P OSM solute-free H 2 0 H 2 0 with solute  This is the H 2 0 “cleared”  Volume in which solutes present would be iso-osmotic compared to plasma. v

19. Free Water Clearance (C H20 ) means to access renal H 2 0 handling, not the usual clearance calculation The C H20 determination considers urine as having 2 parts: Urine Volume solute-free H 2 0 H 2 0 with solute  Can be calculate as Osmolar Clearance C OSM = U OSM · V P OSM Thus…. C H20 = V - C OSM solute-free H 2 0 H 2 0 with solute  This is the H 2 0 “cleared”  Volume in which solutes present would be iso-osmotic compared to plasma. v

20. Free Water Clearance (C H20 ) means to access renal H 2 0 handling, not the usual clearance calculation The C H20 determination considers urine as having 2 parts: Urine Volume solute-free H 2 0 H 2 0 with solute  Can be calculate as Osmolar Clearance C OSM = U OSM · V P OSM Thus…. C H20 = V - C OSM solute-free H 2 0 H 2 0 with solute  This is the H 2 0 “cleared”  Volume in which solutes present would be iso-osmotic compared to plasma. v Note: C H 2 0 could be negative !! This is when very concentrated urine is being produced.

21. Free Water Clearance (C H 2 0 ) means to access renal H 2 0 handling, not the usual clearance calculation The C H 2 0 determination considers urine as having 2 parts: Urine Volume solute-free H 2 0 H 2 0 with solute  Can be calculate as Osmolar Clearance C OSM = U OSM · V P OSM Thus…. C H20 = V - C OSM If… V = C OSM Then… C H20 is zero If… V < C OSM Then… C H20 is negative solute-free H 2 0 H 2 0 with solute  This is the H 2 0 “cleared”  Volume in which solutes present would be iso-osmotic compared to plasma. v If… V > C OSM Then… C H20 is positive Note: C H 2 0 could be negative !! This is when very concentrated urine is being produced.

23. Hormone Released From Release Stimulated byActionResult ↑ RENINKidney -granular cells ↑ sympathetic stimulation ↓BP (via intra-renal sensors) ↓Distal Tube Flow (via macular densa) ↑ circulating ANGII level (a potent vasoconstrictor) ↑ BP ↓ GFR ↑ AldosteroneAdrenal Cortex ↑ ANGII (may result from ↑ renin, ↓BP ) ↑plasma [K] Acts on Principle Cells: ↑ apical Na Channel activity ↑ apical K Channel activity ↑ baso Na-K-ATPase activity ↑ Na reabsorption ↑ K secretion ↑ ANPHeart -atria ↑ blood volume (distention of atria) Vasodilate Afferent Arteriole ↓Na reabsorption (collect. duct) ↓Renin release ↓ALD production ↑ GFR ↓ Na reabsorption ↑ ADHPost Pituitary↑ plasma osmolarity ↓plasma volume Acts on Principle Cells: ↑ apical H20 permeability ↑ H20 reabsorption ↑ PTHParathyroid↓plasma [Ca] ↑ plasma [phos] ↑ Calcitriol production ↑ Ca moving bone to plasma ↑ Ca reabsorption (distal tube) ↓Phos. reabsorption (prox tube) ↑ plasma [Ca] ↓ plasma [phos]