5.5 Renal Tubular Reabsorption and Secretion.pptx

Renal Tubular Reabsorption and Secretion Lecture Outline I. Tubular reabsorption is quantitatively large and highly selective II. Tubular reabsorption includes passive and active mechanisms III. Reabsorption and secretion along different parts of the nephron IV. Regulation of tubular reabsorption V....

Renal Tubular Reabsorption and Secretion Lecture Outline I. Tubular reabsorption is quantitatively large and highly selective II. Tubular reabsorption includes passive and active mechanisms III. Reabsorption and secretion along different parts of the nephron IV. Regulation of tubular reabsorption V. Use of clearance methods to quantify kidney function 1 Renal Tubular Reabsorption and Secretion Lecture Objectives 1. Identify transport mechanisms for tubular reabsorption and secretion 2. Explain how the reabsorption of many solutes is coupled to Na+ 3. Describe water reabsorption along the tubule 4. Explain transport maximum and splay 5. Identify Na+ and H2O transport mechanisms of each tubular segment 6. Explain why the convoluted portion of the distal tubule is called the “diluting segment” 7. Identify the location and the contribution of the NKCC2 transporter 8. Compare the function of principal and intercalated cells of the late distal and cortical collecting ducts 9. Describe the reabsorption of peritubular capillaries 10. List 4 main hormones that regulate tubular reabsorption and explain their action and how they are stimulated 11. Compare the regulation of Na+ and H2O of ADH and Aldosterone 2 References Assigned reading from your text: Hall Chapter 28 3 Reabsorption and Secretion Tubular Reabsorption Basic Principles bular reabsorption is quantitatively large and highly selective ered loads exceed amounts in body Water- 40 L body water; 180 L filtered/day Tubular Reabsorption Basic Principles Kidneys eliminate soluble waste while handling ECF constituents and nutrients Reabsorption of waste products is relatively incomplete Reabsorption of organic nutrients is relatively complete • Not physiologically regulated • Kidneys maintain plasma concentrations Reabsorptive rates for water and many ions are both high and under physiological control • Tubular reabsorption- tubule to interstitium- does not occur by bulk flow • Instead- substances move by: • Diffusion • Mediated transport- requires transport proteins • Movement from interstitium to peritubular capillaries is by bulk flow and diffusion Reabsorption Routes from Filtrate to Interstitium & Peritubular Capillaries  • • • Routes Transcellular- through cell membranes Paracellular- between cells A substance may use both routes  Bulk flow (ultrafiltration) (Pressure gradient) • Hydrostatic and osmotic forces • Reabsorption from interstitium into peritubular capillaries (behave like venous ends) • Bulk flow also governed filtration • Forces that increase reabsorption from renal tubules has the same effect on peritubular capillaries Reabsorption & Secretion from Filtrate to Interstitium & Peritubular Capillaries  By passive and active transport (concentration gradient) • • Primary active requires ATP to transport uphill Primary active transporters in kidney: • Na+-K_-ATPase, H+-ATPase, H+-K+ ATPase, and Ca++ ATPase • By diffusion/osmosis (water diffusion) is downhill • By mediated transport- is transcellular • Substances must first cross the luminal membrane • Finally crosses the basolateral membrane • Basolateral membrane begins at tight junctions Transport of a substance from filtrate to blood may involve both uphill and downhill transport • • • Reabsorption by secondary active transport is usually cotransport Secretion by secondary active transport is usually counter-transport Sodium Reabsorption  Sodium reabsorption uses both passive and active transport • • Sodium moves downhill (passively) into cell through luminal membrane by diffusion/facilitated diffusion Then moves uphill (actively) out of cell across the BL membrane via the Na+/K+-ATPases  The reabsorption of many substances is coupled to the reabsorption of sodium • Cotransported substance moves uphill into the cell via secondary active transport as Na+ moves downhill by the same cotransporter • Glucose, amino acids, and other organic substances reabsorbed this way Water Reabsorption Along Tubule  Passive water reabsorption by osmosis coupled mainly to sodium reabsorption • Filtration and reabsorption- only significant processes affecting NaCl and water excretion  Water permeability varies through tubules • In PT- mostly through aquaporins and tight junctions • In PT and Loop of Henle- high permeability due to expression aquaporin (AQP-1) • Tight junctions have small, yet significant permeability to ions • Solvent drag- water moving through tight junctions may carry solute • In Loop of Henle through collecting tubule • Tight junctions less permeable – despite osmotic gradient • Epithelial cells have a greatly decreased membrane SA • In DTs through collecting tubules- ADH can increase water permeability as needed Glucose Transport Maximum  Transport maximum (Tm ) for mediated transporters • • • Many mediated transport reabsorptive systems have a limit to the amount of material they can transport Binding sites on transport proteins become saturated Filtered load exceeds the ability of the tubules to reabsorb the solute  Example- Glucosuria • Normally, glucose is filtered and 100% reabsorbed • Glucose appears in urine (glucosuria) when filtered load becomes excessive- as it does in diabetes • Also occurs with excess water soluble vitamins • e.g. Large doses of Vitamin C Reabsorption by Passive Diffusion- Example of Urea Reabsorption  Urea reabsorption dependent upon reabsorption of water • Urea freely filtered into tubule • Urea concentration is the same in the tubular and interstitial fluid • As fluid is reabsorbed proximal tubule, urea concentration increases • Higher than interstitial fluid and peritubular capillary urea concentrations • Urea diffuses down its gradient • This mechanism occurs for other lipid-soluble substances (including pesticides) - Reabsorption in the Proximal Tubule (PT)  Reabsorption predominates • Na+ reabsorption varies between along PT • In early PT, Na+ reabsorbed with glucose, AA • In distal half PT, Na+ reabsorption with Cl• Establishes a gradient for Cl- reabsorption • Osmolarity remains same through PT • 65% Na+ and H2O reabsorption • Urea reabsorbed from tubules- less than Cl• Concentration increases as water reabsorbed favoring reabsorption • Permeability to urea varies along tubule • Inner medullary collecting duct has urea transporters • ~50% filtered urea reabsorbed; 50% excreted PT- and Osmotic Diuresis  PT is the site of action of osmotic diuretics • Nonreabsorbed solutes that cause water to remain in the lumen and excreted • Proximal tubule and thin descending limb are the most water permeability- site of action of osmotic diuresis • Mannitol • Glucose from untreated diabetes mellitus 65% 5–7% Na+ 25% 2.4% 0.6% ctive Transport Characteristics in the Proximal Tubule (PT)  PT has high capacity for primary and secondary active transport • Many Na-K-ATPase pumps in BL  Secondary active transport: • SGLT transporters (SGLT1 and SGLT2) are located on the brush border of PT cellsTransport glucose against a concentration gradient into the cell • SGLT2-90% glucose reabsorbed in early PT • SGLT1-10% glucose in late PT • On BL side- facilitated diffusion • GLUT2 and GLUT1 transporters • High capacity for active and passive reabsorption • Cotransport with AA and glucose • Secretion of H+ occurs by counter-transport Loop- Transport Characteristics of Thin and Thick Loops of Henle • • • Thin descending limb: Very permeable to H2O 20% filtered H2O reabsorbed here Few mitochondria • No active reabsorption- passive Thin ascending limb: • Impermeable to H2O) Thick ascending limb: • ~ 25% of filtered load reabsorbed Na+, Cl-, K+, HCO3-,Ca++, Mg++ • Secretion of H+ • Impermeable to H2O Loop- Sodium Chloride and Potassium Transport in Thick Ascending Loop of Henle  NKCC2 Transporter in luminal membrane • Na+, K+, 2 Cl- Cotransporter • Downhill diffusion of Na+ drives reabsorption of K+ • Loop diuretics inhibit the NKCC2 • Loop diuretics-eg furosemide  Sodium-H+ counter-transport in luminal membrane- Secretes H+  Na-K ATPase in BL membrane rly and Late Distal Tubules and Collecting Tubules  • • • • Early DT Functionally similar to TAL Reabsorbs ~5% filtered NaCl Impermeable to H2O Low urea permeability  Late DT • Permeability is ADH dependent • Low urea permeability Early Distal Tubule • First portion of the distal tubule forms the macula densa that provides tubuloglomerular feedback via the JG complex • Early convoluted part of DT is called the “diluting segment”- contains a hypo-osmotic filltrate • Avidly reabsorbs ions • Impermeable to H2O • Similar to late DT • Na-Cl cotransport moves Na+ from lumen into cell • Na-K-ATPase pump transports Na+ out of cell • Cl diffuses out via Cl channels in BL membrane • Thiazide diuretics inhibit Na-Cl cotransporter Late Distal and Cortical Collecting Tubules Principal Cells—Secrete K+  Principal cells under the influence of aldosterone reabsorb Na+ and secrete K+ • Na-K-ATPase in BL membrane • Maintains low intracellular Na+, high intracellular K+ • Favors Na+ diffusion into cell through luminal ENaC leak channels (epithelial Na+) • K+ diffuses into lumen through luminal K+ channel  Site of action of K+ Sparing diuretics • Spironolactone is a mineralcorticoid (aldosterone) receptor antagonist • Inhibits effects of aldosterone • Preserves K+, Excretes Na+ • Amiloride blocks Na+ channels • Directly inhibit Na+ entry  Aldosterone stimulates new ENaC channels Late Distal and Collecting Tubule Type A and Type B Intercalated Cells Intercalated cells are ~35% of cells in collecting tubules/ducts Both cell types can increase in number if needed Type A intercalated cells: Secrete H+ and reabsorb HCO3- in acidosis H+ ATPase (against a large gradient) H-K-ATPase H+ generated by the hydration of CO2 A HCO3- available for reabsorption with each H+ secreted Can reabsorb K+ in acidosis (with aldosterone) Type B intercalated cells Secrete HCO3- and reabsorb H+ in alkalosis Pendrin is the Cl-HCO3- transporter on Type B cells Can secrete K+ in alkalosis Transport Characteristics of Medullary Collecting Ducts uboidal epithelium with few mitochondria: ater permeability controlled by ADH ea transporters facilitate urea diffusion into interstitium to concentrate u an secrete H+ ions against a large gradient Normal Renal Tubular Na+ (and Water) Reabsorption- and other Solutes 5–7% 65% Na+ 25% 2.4% 0.6% Regulation of Tubular Reabsorption  Glomerulotubular Balance- Tubules can increase reabsorption rates in response to increased tubular load maintains Na+ and volume homeostasis in distal tubules  Compare to tubuloglomerular feedback that maintains GFR  Peritubular physical forces • Increased arterial pressure raises peritubular capillary pressure; • Afferent and efferent arterioles reduce peritubular capillary hydrostatic pressure • Colloid osmotic pressure of these capillaries increases reabsorption Tubular reabsorption Tubular load Regulation of Tubular Reabsorption-Hormones  Hormones • Aldosterone controls ECF volume – influences Na+ and H2O reabsorbed together • Stimulated by increased ECF K+, decreased Na+, and increased angiotensin II (in low volume states) • Aldosterone deficit (Addison’s syndrome) causes Na+ loss and K+ accumulation • Excess aldosterone (Conn’s syndrome) causes Na+ retention and K+ loss • Angiotensin II- increases Na+ and H2O reabsorption • Stimulates aldosterone secretion • Constricts efferent arterioles • Stimulates Na+ reabsorption by stimulating multiple transporters • Antidiuretic hormone (ADH)- controls ECF osmolarity- only affects H2O reabsorption (not Na+) • Increases water permeability in DT, collecting tubule and duct • Low permeability without ADH- causes the excretion of large amounts dilute urine • • SIADH- pathologic oversecretion can cause fatal hyponatremia Central diabetes Insipidus- insufficient ADH- hyperosmolarity, hypernatremia, increased thirst Regulation of Tubular Reabsorption- SNS and MAP • Sympathetic nervous system activation decreases Na+ and H2O excretion • Increases tubular reabsorption by alpha-adrenergic receptors on tubular epithelium • SNS stimulation increases renin release and angiotensin II formation • Surgical stress can cause SNS activation, RAS activation, and ADH production • Decreases RBF, decreases GFR, decreases urine output • Systemic arterial pressure (pressure natriuresis occurs when autoregulation impaired in renal disease) Increases in blood pressure of 30-50 mmHg can increase Na+ excretion 2-3X • Independent of SNS • Na+ excretion -pressure natriuresis and • H2O excretion - pressure diuresis • Antidiuretic Hormone (ADH) Controls ECF Osmolarity ADH is synthesized by the supraoptic and paraventricular nuclei of the hypothalamus Stored in and secreted by the posterior pituitary after hypothalamic osmoreceptors stimulated • 1% deviation plasma osmolarity will vary ADH secretion • Most potent stimulus for ADH secretion- reduced plasma volume of more than 10% • Nicotine stimulates secretion; Ethanol inhibits secretion Vasopressin preserves volume and is a potent vasoconstrictor • V1 receptors mediate vasoconstriction • V2 receptors mediate renal water retention by inserting aquaporins in DT and collecting tubules • ADH binds to V2 receptors, increases cAMP and activates protein kinases • Inserts AQP2 channels into luminal membrane • AQP3 (&4) - constitutive water channels in the basolateral membrane Quantifying Tubular Function & Fractional Excretion of Na+  Rate of urinary excretion of a substance can be affected by: • Glomerular filtration • Tubular reabsorption • Tubular secretion  Definitions: • Filtered load- the amount of a substance filtered per unit time • Excretion rate- amount excreted per unit time • Fractional excretion (FE) expresses solute excretion as a percentage of filtered load • FE is useful- changes reflect altered tubular transport (not just GFR) • FE is known as the clearance ratio (ratio of solute clearance to creatinine clearance)  Calculating FENA is useful in acute renal failure (ARF) to determine if ARF is due to prerenal (hypovolemia) versus renal (acute tubular necrosis) pathology • Prerenal FENA will be low (<1%) • FENA >2% is due to reduced ability of damaged tubules • Diuretics interfere with tubular reabsorption of Na+ • Use FE urea instead of FENA. Using Clearance to Estimate GFR • For a substance that is freely filtered, but not reabsorbed or secreted (eg inulin) renal clearance is equal to GFR • Clearance is the volume of plasma cleared (rendered free) of a given substance per unit time (often per 1 minute) =. ml/min • Calculated as the ratio of urinary excretion rate to plasma concentration Cs = (Us × V)/ Ps Where : Cs = clearance of substance S Ps = plasma conc. of substance S Us = urine conc. of substance S V = urine flow rate 29 Using Clearance to Estimate GFR • Inulin can be used to estimate GFR since freely filtered – Not reabsorbed or secreted – It is not usually used clinically since it must be intravenously infused • Plasma creatinine is a direct index of GFR; increased with low GFR – Creatinine production is constant, excretion rate varies with GFR – Overestimates GFR by ~ 10% since it is secreted into the proximal tubule – Used to determine the stages of renal failure 30 1. A patient with frequent urination hasthe followinglab values. Hypotension=BP88/40 mmHg Plasma sodium=165 mmol/L Normal plasma potassium=4.4 mmol/L Low urine osmolarity specific gravity 1.003 HR=115 bpm What is the most likely cause of her hypernatremia? A. B. C. D. Primary aldosteronism Diabetes mellitus Diabetes insipidus Simple dehydration due to heavy exercise 2. A patient with renal artery stenosis, severe hypertension, and GFRis reduced to 25% of normal. Which of the followingchangesisexpected in thispatient? A. B. C. D. A large increase in plasma sodium concentration A reduced urinary sodium excretion A reduced urinary creatinine excretion to 25%of normal An increase in serum creatinine to about four times normal 3. Which of the followingtendsto decrease potassiumsecretion by the cortical collecting tubule? A. B. C. D. Increased plasma K+concentration A diuretic that decreases proximal tubule Na+reabsorption A diuretic that inhibits the action of aldosterone Acute alkalosis 4. The maximumclearance rate possible for a substance totally cleared fromthe plasma isequal to which of the following? A. B. C. D. GFR Filtered load of that substance Urinary excretion rate of that substance Renal plasma flow 5. Which change would you expect to find in a dehydrated person deprived of water for 24 hours? A. B. C. D. Decreased plasma renin activity Decreased plasma antidiuretic hormone concentration Increased plasma atrial natriuretic peptide concentration Increased water permeability of the collecting duct 31