Sodium Handling and Diuretics

1. Sodium Handling and Diuretics

2. Learning objectives 1. Describe the normal whole-body daily sodium balance. 2. Describe the contribution of the major nephron segments to the reabsorption of filtered salt and water. 3. Outline the mechanisms for NaCl absorption along the proximal tubule and describe the changes that occur along the length of this segment. 4. Describe the mechanism of NaCl absorption in the thick ascending limb of Henle’sloop, the distal convoluted tubule and in renal principal cells. 5. Describe the molecular biology of the major sodium transport proteins in the nephron. 6. Summarize the main neurohumoral factors which regulate NaClreabsorption along the nephron.

3. Sodium Homeostasis • The normal concentration range of sodium in the plasma is 136 - 145 milliequivalents per liter. 145 136 • Hypernatremia • • what will happen if the sodium concentration of the blood plasma increases, as in hypernatremia. • • What effect would this increase in sodium concentration have on the cells that are bathed by the interstitial fluid? • ___ Cells swell • ___ Cells shrink • • The high concentration of sodium in the extracellular fluid exerts osmotic pressure and helps determine the fluid levels in the intracellular space. • Hyponatremia • • What effect would this decrease in sodium concentration have on the cells that are bathed by the interstitial fluid? • ___ Cells swell • ___ Cells shrink • • The water moves into the cell, and the cell expands slightly.

4. Roles of Sodium in the Body • • nerve impulse conduction and muscle contraction, • primary regulator of water movement in the body because water follows sodium by osmosis. • • If sodium levels in the plasma change, those changes determine fluid levels in the other compartments. Causes and Symptoms of Hypernatremia Which of these reasons would most likely cause hypernatremia in the marathon runner? ____ Too much sodium added ____ Too much water lost Symptoms of hypernatremia include non-specific signs of central nervous system dysfunction such as confusion and lethargy, and in severe cases, seizures and death. • What do you think causes these symptoms? ___ Neurons shrink ___ Neurons swell What will happen to urine output?  Decreases • When plasma osmolarity increases, antidiuretic hormone is released, resulting in reabsorption of water and decreased urine output.

5. Sodium Balance

6. Overview of Renal Sodium Handling NaCland water are filtered at the highest rates. Therefore there is an enormous amount of water and sodium reabsorption. Reabsorptionof water and sodium are related- ‘water will follow sodium’ 2) transport of sodium (down its electrochemical gradient) is linked to essential tubular reabsorptive and secretory processes for many other substances. 3) mechanisms of NaClreabsorptionare modified clinically by diuretics.

7. Where Does Na+ Reabsorption Occur? FE = 10% [Na+]=145 FE = 3% FE = 35% FE = 0.1 - 2% [Na+] units = mmole/L FE= Fractional excretion

8. Mechanisms Of Sodium Reabsorption The Na+/K+-ATPase Drives Na+Reabsorption All Along The Renal Tubule Lumen Blood Na+ 3Na+ ATP ADP 2K+ diuretics Na+

9. In Early Proximal Tubule Na+ Absorption Is Linked To Nutrient Transport….. Lumen Blood 3Na+ Na+ ATP ADP 2K+ nutrient Nutrient (a.a & gluc.) Familial renal glycosuria – SGLT2 mutations Cystinuria – dibasic amino acid carrier Hartnup’s disease – neutral amino acids

10. But..Far More Na+ Than Nutrient Must Be Absorbed! Blood Lumen Cl- Na+ K+ NHE3 Cl- H+ 3Na+ ATP Na+ and Cl- ADP 2K+ Na+ Base- 3 HCO3- Cl- Ang II & NE target NHE3

11. Absorption Mechanisms Change Along The Proximal Tubule 2.0 1.5 Cl- [TFx/Px] Na+ 1.0 osm HCO3- 0.5 Glucose/amino acids 0.0 Length of proximal tubule

12. Na+ Uptake In The TALH Is Via A Cotransport Mechanism Blood Lumen 3Na+ Na+ NKCC2 2Cl- 2K+ K+ Cl- ROMK CLC-Kb + cations Na, Ca and Mg Mutations in any of NKCC2, ROMK or CLC-Kb = BARTTER’S SYNDROME ADH targets NKCC2 & ROMK ‘loop diuretics’ Bumetanide & Furosemide block NKCC2

13. Where Does Na+ Reabsorption Occur? FE = 10% [Na+]=145 FE = 3% FE = 35% FE = 0.1 - 2% [Na+] units = mmole/L

14. Early Distal Tubule Uses Na/Cl Cotransport For Na+ Absorption Lumen Blood 3Na+ Na+ NCCT 2K+ Cl- Cl- NCCT mutations cause GITTELMAN’S SYNDROME Thiazide Diuretics block NCCT

15. Na+ Entry In The Collecting Duct Is Via An Ion Channel Lumen Blood Principal cell Na+ ENaC 3Na+ K+ ROMK 2K+ ENaC gain of function = LIDDLE’S SYNDROME ENaC loss of function = PSEUDOHYPOALDOSTERONISM (PHA) Aldosterone activates ENaC & ROMK while Amiloride like diuretics block ENaC

16. Summary • Most Na+ reabsorption occurs in the proximal tubule • “Fine-tuning” of Na+ reabsorption occurs in the late distal tubule and collecting duct

17. But how do we regulate overall Na+ levels? • Glomerular Tubular Balance • Neurohormonal mechanisms

18. Glomerulotubular Feedback

20. Angiotensin II Norepinephrine Dopamine Aldosterone ADH PGE2 ANP Stimulate Na+ Reabsorption Inhibit Na+ Reabsorption Neurohumoral Regulation Of Na+ Reabsorption:

21. Angiotensin II Major effect at the proximal tubule Lumen Blood Na+ 3Na+ NHE3 ATP ADP H+ 2K+ Na+ Na+ Base- ? ? 3 HCO3- Cl-

22. Norepinephrine Via α1 receptors Major effect at the proximal tubule Lumen Blood Na+ 3Na+ NHE3 ATP ADP H+ 2K+ Na+ Na+ Base- ? ? 3 HCO3- Cl-

23. Makes interstitial fluid more hypertonic. Important for concentrating urine ADH Has an effect in TALH Lumen Blood 3Na+ Na+ NKCC2 2Cl- 2K+ K+ Cl- ROMK CLC-Kb Na+ + cations

24. Aldosterone Effect in Collecting Duct Lumen Blood Na+ ENaC 3Na+ K+ ROMK 2K+ Na+ Principal Cell

25. Atrial Natriuretic Peptide Effect in Collecting Duct Lumen Blood Na+ ENaC 3Na+ K+ ROMK 2K+ Some question over is it ANP or Urodilatin involved in this response

26. The movement of sodium across the nephron is directly associated with the movement of water. Therefore sodium movement has an effect on urine concentration and water loss or………… Water follows sodium