Physiology Review Sheet - University of Michigan



Physiology Review Sheet

Renal Physiology – Part I

I. Renal system overview

a. general

i. portal system: glomerular capillary is between the afferent and efferent arterioles

ii. afferent and efferent a. are major sites of resistance

iii. post-glomerular flow

1. outer and mid-cortex: form peritubular capillaries

2. juxtamedullary nephrons: form vasa recta

3. capillaries found between descending and ascending vasa recta

b. nephron #

i. ~800,000 / kidney (1.5-2 million total for 2 kidneys)

ii. can lose ~ 85% of nephrons before experiencing symptoms

c. proximal tubule

i. S1 segment

1. many microvilli and mitochondria

2. lots of active transport

3. water and solute and most of filtered organic material is reabsorbed here

ii. S2 segment

1. fewer microvilli and mitochondria

2. still have active transport

3. volume and solute still reabsorbed

iii. S3 segment

1. aka pars recta, aka proximal straight tubule

2. even fewer microvilli and mitochondria

3. some active transport

4. secretion of weak acids/bases

5. passive reabsorption of Na+ and water

d. Loop of Henle

i. just the thin limb (international committee definition)

1. thin descending limb (tDL): begins at junction of outer and inner stripe of outer medulla

2. thin ascending limb (tAL): ends at junction between inner medulla and inner stripe of outer medulla

ii. types of nephrons

1. cortical (short-looped): 85%

2. juxtamedullary (JM) (long-looped): 15%

iii. cells: few microvilli and mitochondria

iv. function:

1. mostly passive transport

2. tDL: very permeable to water, impermeable to solute

3. tAL: impermeable to water, permeable to solute

4. role in forming medullary osmolar gradient

e. distal tubule

i. medullary thick ascending limb (TAL)

1. major site of Na+ (20-30% of filtered), K+, and Cl- reabsorption (also Mg2+, Ca2+)

2. primary mechanism of formation of medullary osmolar gradient

3. uses Na-K-2Cl transporter (cotransport)

a. inhibited by loop diuretics (excretion of lots of Na+)

ii. cortical thick ascending limb (aka cortical diluting segment): see medullary TAL

iii. distal convoluted tubule (DCT)

1. begins at juxtaglomerular apparatus

a. macula densa (modified tubular cells)

b. juxtaglomerular cells (modified smooth muscle of afferent a.)

c. Lacis cells

2. JG apparatus function

a. macula densa: monitor delivery rate of Na+

b. JG cells secrete renin when NaCl ↓ (eg. BP ↓)

i. renin will cause ↑ AII ( ↑ aldo ( ↑ BP

3. DCT function

a. coupled NaCl reabsorption via coupled NaCl pump on apical membrane

i. inhibited by thiazide diuretics

b. major site of Ca2+ reabsorption via Ca2+ ATPase on apical membrane

i. activated by parathyroid hormone and activated vitamin D3

ii. activated by thiazide diuretics

f. collecting duct

i. 3 sections

1. cortical collecting duct (CCD)

2. outer medullary collecting duct (OMCD)

3. inner medullary collecting duct (IMCD)

ii. site of

1. Na+ and water reabsorption

2. K+ and H+ secretion

iii. hormonal regulation

1. aldo (CCD)

2. ADH (all 3 regions)

3. ANP (OMCD & IMCD)

g. vascular tubular relationships

i. post-glomerular blood of cortical nephrons: perfuse proximal and distal tubules of parent glomerulus

ii. post-glomerular blood of mid-cortical nephrons: perfuse proximal and distal tubules of JM nephrons

iii. post-glomerular blood of JM nephrons

1. don’t perfuse proximal and distal tubules at all

2. eff. a. of JM nephrons descend as vasa rectae and perfuse only loop and MCD

3. major effect on clearance of weak organic acids/ bases

II. kidney function

a. filtration

i. formation of ultrafiltrate of plasma in glomerulus (cortex only)

ii. passive

1. balance of Starling’s forces between glomerular capillary and Bowman’s space

2. Kf

b. reabsoprtion

i. movement of fluid and/or solute from lumen into peritubular capillaries or vasa recta capillaries

ii. passive for water

iii. can be passive, active, or a combination

iv. regulated by hormones: determines final urine

c. secretion

i. movement of solute from peritubular plasma to lumen

ii. almost always active

iii. e.g. weak acids/bases, H+, K+

III. Renal Clearance

a. overview

i. must be obtained at steady state

ii. definition: volume of plasma cleared of a given solute / unit time

1. Cx = (Ux x Vx) / Px

2. Clearance = (urine concentration x urine flow rate) / plasma concentration

iii. reminder of major plasma concentrations

1. K+ = 4mEq/L

2. Na+ = 140 mEq/L

3. Cl- = 100 mEq/L

4. HCO3 = 24 mEq/L

5. glucose (glc) = 90 mg%

6. protein = 8 g%

7. osmolarity = 280 mOsm/L

b. clearance of inulin

i. inulin

1. ECF marker

2. freely permeable across capillaries, doesn’t cross cell membranes

3. in kidney

a. freely filtered

b. NOT reabsorbed

c. NOT secreted

ii. amount filtered/unit time = amount excreted / unit time

1. GFR x Pinulin = V x Uinulin

iii. Cinulin = GFR (same is true for clearance of any substance freely filtered, not reabsorbed, and not secreted)

1. anything > Cinulin : net secretion

2. anything < Cinulin: net reabsorption

c. Fun with numbers

i. normal GFR = 120 mL / min

1. ↓ with age to 100 mL/min by age 60

2. nephrogenesis complete by 36 weeks gestation

a. GFR ↑ for first 4 months (more so than kidney mass)

b. GFR levels off until early 20s, then ↓

ii. form 170-180 L filtrate/d

1. drink 1-2 L/d = amount excreted

2. amount filtered by ~10% due to secretion in proximal tubule (relatively insignificant)

2. GFR x PCr = UCr x V = K

3. creatinine production rate (K) = 1.2 mg/min

4. normal PCr = 1 mg%

5. production and excretion are constant

a. if GFR ↓, PCr must ↑ (over ~3-5d)

b. for a few days production > excretion and body ↑ creatinine stores

e. renal plasma flow (RPF)

i. Fick principle

1. RPFa x Pa = (RPFv x Pv) + (U xV)

2. RPFa (renal artery) ≈ RPFv (renal vein) because cations in filtrate

b. anions in filtrate > anions in plasma

3. TF / P ratio (tubular fluid : plasma)

a. Na+ in glomerulus = 0.95

b. Cl- in glomerulus = 1.05

v. Starling forces

1. forces

a. hydrostatic pressure in glomerular capillaries (HPc)

i. 50-60 mmHg in JM

ii. 40-50 mmHg in cortical

iii. ↓ along capillary by ~ 2 mmHg

b. hydrostatic pressure in Bowman’s space = 10 mmHg (uniform) (HPbs)

c. COP in glomerulus

i. determined by FF

ii. significantly ↑ along capillary

d. COP in Bowman’s space = 0

e. Kf is high

2. GFR = Kf (∆P – COPc)

a. ∆P = HPc – HPbs

b. Kf = ultrafiltration coefficient

i. permeability factor (size and # of pores)

ii. variable

1. AII will increase by changing contractile state of mesangial cells (can ↑ pore size)

2. a change in Kf may or may not change GFR

vi. filtration pressure disequilibrium

1. net ultrafiltration P at end of capillary (∆P > COP)

a. along capillary, ∆P falls a little (↓ HPc) and COP ↑ a fair amount (due to loss of filtrate)

b. PUF ↓, but is still there at the end of the capillary

c. GFR = Kf x PUF

2. effects of changes in . . .

a. vasodilation of aff a: ↓Raa ( ↑ HPc ( ↑ GFR (large change)

b. vasoconstriction of eff a: ↑ Rea ( ↑ HPc ( ↑ GFR (small change)

c. ↑ RPF: shifts COP curve to right (slower rate of ↑ in COP); smaller ↑ in GFR because COP curve is flatter (diffusion-limited)

d. ↑ Kf: small ↓ in PUF (due to flatter COP curve) so won’t offset change in Kf . . . significant ↑ in GFR

vii. filtration pressure equilibrium

1. lack net ultrafiltration P at end of capillary (∆P = COP)

a. when ∆P = COP, filtration stops and reabsorption occurs over the rest of the capillary

b. ↓ in ∆P, ↑ in COP

c. perfusion limited

2. effects of change in . . .

a. vasodilate aff a.: ↓ Raa ( ↑ HPc ( ↑ GFR (large change)

b. vasoconstrict eff a: ↑ Rea ( ↑ HPc ( ↑ GFR (small change)

c. ↑ RPF: shifts COP curve to right (slower rate of ↑ in COP); ↑ PUF ( ↑ GFR (significant) (perfusion limited)

d. ↑ Kf: shift COP curve to left (more rapid efflux of fluid causes more rapid ↑ in COP); ↓ PUF offsets ↑ in Kf ( GFR ↔

viii. glomerular hyperfiltration

1. possible cause of ↓ GFR with age

2. ingested protein causes ↑ in circulating AA

a. ↑ GFR for 1-2 h ( scars glomeruli (glomerular sclerosis)

b. may be growth hormone mediated

V. Tubular Events

a. active transport

i. energy dependent

ii. high temperature dependency (high Q10 – change for every 10˚ changed)

iii. saturation kinetics (competitive and non-competitive inhibition)

iv. transport maximum (Tm) for reabsorption and secretion

b. S1 of proximal tubule

i. Na/K ATPase

1. basolateral membrane

2. driving force for secondary active transporters

3. creates Na+ gradient between lumen and cell

ii. Na cotransporters

1. use Na+ gradient from Na/K pump to move glc, AA, etc into cell

2. luminal

3. SGLT2

a. Na-glc transporter

b. apical membrane

c. Na+ moved down concentration gradient

d. glc moved against concentration gradient

e. not regulated by insulin

f. SGLT1: similar but in later prox tubule

g. SGLT4: insulin-sensitive (little in kidney)

h. GLUT2 transports glc out of cell into peritubular capillary

i. NOT a Na+ cotransporter

ii. NOT insulin sensitive (GLUT4 IS and is in muscle)

c. S2 and S3 of proximal tubule

i. secretion into proximal tubule of weak organic acids/bases; penicillin and its derivatives

ii. Tm limited

iii. extraction ~90%; C ≈ RPF

d. TmG (transport max for glucose)

i. amount of glc filtered – amount reabsorbed = amount excreted

1. (GFR x Pglc) – amount reabsorbed/time = Uglc x V

2. normally none excreted, so amount filtered = amount reabsorbed

3. normally never exceeds reabsorption capacity for kidney

ii. amount filtered ↑ linearly with Pglc

iii. not a variable – TmG = 360 mg/min for all

1. renal threshold: Pglc when glc first appears in urine: 180mg%

a. if reach renal threshold for glc, amount excreted ↑ linearly with Pglc (slope = GFR); Cglc can approach GFR at very high concentrations

b. below predicted value (300 mg%)

i. splay – difference between predicted and actual renal threshold

ii. TmG is average for 200 million nephrons, not all have same threshold

iv. not reason for glucosuria in diabetes because SGLT2 and GLUT2 aren’t insulin sensitive – but if they are defective, they can cause glucosuria

v. related to tubular mass (# of transporters): if donate a kidney, cut TmG in half, but renal threshold is same

vi. kidney doesn’t regulate Pglc . . . does function to prevent sugar loss

e. TmPAH (secretory max)

i. amount filtered + amount secreted = amount excreted

1. (GFR x PPAH) + amount secreted = UPAH x V

ii. clearance approaches GFR at high concentrations and approaches RPF at low concentrations in plasma

iii. clearance of avidly secreted drugs is like PAH (e.g. ampicillin)

1. Tmamp = 1 mg/ min

2. at low dose . . . 20% filtered, 80% secreted → completely cleared in 30 min

3. give high dose (above Tm) to decrease clearance

VI. The Proximal Tubule

a. major functions

i. 60-70% initial filtrate reabsorbed (isosmotic)

1. 60-70% filtered Na+, K+ and Ca2+ reabsorbed

2. most of filtered organic solvent (AA, glc, HCO3-) is completely reabsorbed in S1

ii. secretion of organic acids/bases

b. water reabsorption

i. 60-70% reabsorbed along whole proximal tubule

1. water passively follows Na+ in proximal tubule (highly permeable to water due to high # of aquaporin channels (AQP1))

a. lumenal filtrate is a few mOsm below plasma: enough to cause lots of water reabsorption (within error range of osm determination)

b. TF/P = 1 for osmolar ratio along entire proximal tubule (not influenced by hydration state)

c. 2 step reabsorption

i. water moves into ISF (Na dependent)

ii. absorption from ISF into peritubular capillaries (Starling forces: HPc is low and COP is high)

d. in S2 and S3, TF concentration of AA, glc, and HCO3- is low, but plasma concentrations are relatively high ( osmotic force for water reabsorption

2. small volume flow (30-40%) enters loop

a. maintained constant via TG feedback because loop and distal nephron can’t handle large volume flows

ii. steady state: amount of inulin filtered = amount passing any point along the tubule

1. SNGFR x Pinu = VTF x TFinu

2. only true up to level of collecting duct because other nephrons will then contribute to fluid

3. ↑ in TFinu = fluid reabsorption

4. for freely filtered, non-reabsorbed, non-secreted

iii. (Pinu / TFinu) = (VTF / SNGFR)

1. ratio tells amount of fluid reabsorbed up to that point along the tubule

2. usually P/Tinu is 1/3 at end of proximal tubule, reflecting 60-70% fluid reabsorption

3. regulated mostly by adjustments in distal nephron, some by AII and NE

iv. creatinine does same thing as inulin

v. urea concentration increases, but not as much as inulin because some urea moves out of the tubule

c. Na+ reabsorption

i. Na/K ATPase on basolateral membrane creates a Na gradient between cell and lumen (drives transport)

ii. Na TF/P = 1.0 along entire tubule because as Na moves out, water follows (isosmotic)

iii. Na cotransporters

1. for glc and AA

2. secondary active transport

3. electrogenic pumps: generate –2mV transtubular potential which helps anion absorption in S1 segment

iv. Na-H antiporter (NHE-3)

1. in S1

2. secretes H+ into lumen (along with H+ ATPase pump)

a. lowers pH to ~7.0

b. AII, NE, and acidosis stimulate both H+ pumps (↑ Na+ reabsorption)

c. H+ are substrates for activities in lumen

i. NH3 ( NH4 (pK = 9.0)

1. S1 secretes NH3 which is converted to NH4 by secreted H+ in lumen of proximal tubule

2. important for H+ excretion and acid/base balance

ii. HPO42- ( H2PO4- (pK = 6.8)

1. formation of titratable acid

2. same occurs with other weak acids

3. contributes to acid/base balance

iii. HCO3- reabsorption

1. [HCO3-] filtrate = 24 mEq/L

2. 90% reabsorbed in proximal tubule (mostly S1)

3. depends on H+ secretion

a. converts filtered HCO3- ( H2CO3

b. H2CO3 ( CO2 and water by carbonic anhydrase on brush border

c. CO2 and water diffuse into cell where HCO3- is remade and exits cell basolateral membrane via . . .

i. AE1: Cl-/anion exchanger

ii. NBC: Na/HCO3- cotransporter

d. Cl- reabsorption

i. [Cl-]filtrate = 100 mEq/L

ii. S1: Cl- reabsorbed, but not nearly as much as was filtered

1. TF/P at end of S1 = 1.2

2. due to preferential reabsorption of organic solute

iii. S2 & S3 : significant increase in permeability to Cl-

1. Cl- diffuses passively out of lumen down its concentration gradient

a. due to active stuff in S1

b. +2 mV transtubular potential develops in late proximal tubule (passive reabsorption force for cations)

2. slight decrease in TF osmolarity due to loss of Cl- ( water follows via AQP1 channels (non-regulated)

e. solvent drag

i. molecules passively reabsorbed with reabsorption of water and Na

ii. paracellular route

iii. K+

1. 60-70% reabsorbed in proximal tubule

2. passive solvent drag and suspected active component

3. slightly more K+ than Na+ and water is reabsorbed here

iv. Ca2+ (60-70% reabsorbed in proximal tubule)

f. weak organic acid and base secretion

i. S2 & S3

ii. αkg antiporter on basolateral membrane, then passive diffusion into lumen

g. GT balance

i. fractional reabsorption of Na+ and water is relatively constant despite changes in GFR

1. if GFR increases, absolute reabsorption in proximal tubule must increase to keep fractional reabsorption constant

2. may be due to large capacity for reabsorption of organic solute in early proximal tubule

h. urea

i. moderately permeable in proximal tubule

1. concentration will begin to increase as water is reabsorbed, but when reaches a certain point, will diffuse passively into cells

2. TF/P is between inulin and Na+

ii. blood urea nitrogen (BUN) = aka Purea

1. normal = 12 mg% (contributes to osmotic pressure of plasma)

2. increased by

a. increased protein intake

b. decreased urine flow rate (dehydration)

c. decreased GFR

d. fever, hemolysis

3. determine hydration status

a. dehydration (decrease V) ( decreased Curea (more reabsorbed) ( increase BUN

i. note: GFR and Pcr don’t change

ii. BUN: creatinine increases

1. normal = 12mg%:1mg%

2. dehydration = >20mg%:1mg% (prerenal azotemia)

VII. Loop of Henle: Generation of Osmolar Gradient

a. can produce dilute (50mOsm/L) or concentrated (1200mOsm/L) urine

b. larger medulla indicates greater concentrating ability

c. medullary osmolar gradient

i. cortex, ISF, ICF: 280 mOsm/L (ECF ( 150 mM NaCl)

ii. outer medulla: 400 mOsm/L (ECF ( 200 mM NaCl)

iii. inner medulla: 1200 mOsm/L (ECF ( 300 mM NaCl & 600 mM urea)

d. counter current flow system

i. for thermal energy

1. ascending and descending limbs allow transfer, insulated system, flow rate allows equilibrium

2. some heat is trapped

ii. erroneous postulation for kidney: active solute (Na+) extraction from tAL & TAL without water following leads to Na (and Cl) diffusing into DL . . . hypotonic fluid would enter early DCT

1. correct features

a. tAL and TAL are impermeable to water under all conditions

b. there is active transport in the TAL

c. hypotonic fluid does enter the DCT (100 mOsm/L)

2. errors

a. no active transport in tAL

b. does not mention that urea contributes to gradient

iii. countercurrent multiplication without active transport in tAL

1. tDL transport and permeability

a. high water permeability under all conditions due to AQP1 pores

b. no active reabsorption or secretion

c. not permeable to any solute (not sure how permeability to Na and urea is involved, so ignore)

d. consequences:

i. water loss from nephron due to very high osmolar concentration in papilla (1200 mOsm/L)

ii. fluid at the turn of the loop will equilibrate to the same concentration as ISF – 1200 mOsm/L

iii. creatinine TF/P increases x 4 due to water loss without creatinine loss

1. TF/P at end of proximal tubule = 3:1

2. TF/P at tip of loop = 12:1

3. >90% of filtered volume has been reabsorbed by tip

iv. NaCl TF/P increases x 4 (150mM ( 600mM)

1. note: at end of proximal tubule Na+ is still 140mEq/L, but Cl- has increased by 20% to 120mEq/L (not exactly equal)

2. at the tip of the loop there is a concentration gradient for NaCl to want to move out of the TF into ISF (600mM ( 300 mM) – the NaCl is only 600 mM because only half of the 1200mM is due to NaCl

2. tAL transport and permeability

a. impermeable to water – no AQP channels

b. no active transport

c. very permeable to NaCl

i. Cl- channel on apical and basolateral surface of cell (CLCK1)

d. moderately permeable to urea

e. consequences:

i. NaCl passively diffuses down concentration gradient into ISF via CLCK1 along entire tAL

ii. [Na] and osmolar concentration in TF decrease; same concentrations in ISF increase

iii. solute loss from TF without water following ( form dilute urine

iv. fluid leaving tAL is hypotonic to ISF (not to plasma)

v. some urea diffuses down its concentration gradient into TF (exits IMCD and enters AL)

3. TAL transport and permeability

a. impermeable to water always

b. Na-2Cl-K transporter on apical membrane (NKCC2)

i. inhibited by loop diuretics (furosemide and bumetamide ( aka bumetamide sensitive cotransporter (BSC))

ii. secondary active transport

iii. reabsorb 20-30% of filtered Na+ here

iv. “single effect mechanism” ( without this, there would be no medullary osmolar gradient

c. K+ movement

i. Na-2Cl-K pump moves K+ into cells

ii. K+ diffuses back into lumen via renal outer medullar K+ channel (ROMK)

iii. creates a positive trans-tubular potential (10-15 mV) ( drives paracellular reabsorption of most K+ and Na+, Mg+, Ca2+ (20-30%)

d. CLCK2 channel: exit for all Cl- from cell to blood

e. NHE (Na-H exchanger) on apical membrane: secretes H+

f. CA (carbonic anhydrase) on brush border: reabsorb HCO3-

g. ADH influence on TAL cell: increases expression of NKCC2, ROMK, & CLCK2 (all present at basal levels without ADH)

h. Bartter’s syndrome

i. mutation in NKCC2, ROMK, or CLCK2

ii. looks similar to loop diuretic treatment

4. DCT permeability and transport

a. impermeable to water and urea always

b. NaCl cotransporter

i. net solute extraction

ii. 5% filtered Na+ reabsorbed here

iii. TF enters DCT @ 100 mOsm/L and leaves even more hypotonic

iv. thiazide diuretics work here

5. CCD & OMCD

a. ADH regulates water permeability by altering expression of AQP-2 channels ( without ADH, impermeable to water

b. always impermeable to urea

6. IMCD

a. ADH regulates water permeability by altering expression of AQP-2 channels

b. ADH regulates urea permeability by changing expression of UT channels

e. development of the gradient

i. start:

1. uniform osmolar gradient in medulla and cortex (300 mOsm/L)

2. lots of ADH

ii. first pass through medulla: up to beginning of TAL, no change in TF because all events prior require a gradient

iii. first pass TAL

1. max activity of NKCC2 due to ADH: net solute extraction without water following

2. slightly hypotonic solution presented to DCT (~200 mOsm/L)

iv. first pass DCT

1. NaCl cotransporter extracts more Na, but NO water or urea

2. reabsorbs 5% of Na

3. fluid moves on slightly more hypotonic

v. first pass CCD

1. lots of AQP-2 due to ADH: equilibration between TF and ISF due to water movement (300 mOsm/L)

2. no permeability to urea: TF [urea] increases

3. Na+ reabsorbed, K+ and H+ secreted ( regulated by aldosterone

vi. first pass OMCD

1. receives smaller volume of isosmotic fluid

2. TF passes by region of ISF high in Na+ due to NKCC2 of TAL: draws water osmotically into ISF (high permeability due to high AQP-2 due to ADH)

3. urea is impermeable: TF [urea] increases

vii. first pass IMCD

1. receives smaller volume of high [urea] TF

2. ADH increases UT ( high urea permeability: urea goes down concentration gradient into ISF

viii. 2nd pass tDL

1. water leaves TF osmotically due to high [NaCl] in outer medulla (from NKCC2 in TAL) and in inner medulla due to high [urea] (from diffusion out of IMCD)

2. no solute permeability

ix. 2nd pass at tip of loop and tAL

1. fluid now concentrated due to loss of water in tDL

2. NaCl is passively reabsorbed due to concentration gradient

3. no water permeability

4. urea enters TF down its concentration gradient

5. fluid entering TAL has a significantly decreased volume flow, so the effectiveness of NKCC2 increases

f. role of the vasa recta

i. form countercurrent exchange

ii. post-glomerular vessels: high COP and low HPc favors reabsorption of Na, urea, and water

iii. solutes recycle here

1. diffuses out of ascending limb of recta and into descending limb (both permeable)

2. water stays in plasma due to high COP

VIII. Distal nephron: homeostatic mechanisms

a. Na+ balance (see notes on clearance above)

i. amount Na ingested = amount excreted

1. 250 mEq/d ( hypertension

a. not the same value for all

b. salt sensitive ( hypertension at lower intake levels

ii. excess Na also linked with increased Ca2+ loss

1. Ca2+ passively follows Na and water out of the tubule

2. increased sodium due to high soda intake ( increased phosphate ( inhibits vitamin D3 and Ca2+ reabsorption in gut

iii. filter 25000 mEq/d ( amount ingested and excreted is very small in comparison

iv. Na+ reabsorption

1. >99% Na reabsorpbed

a. 70% in proximal tubule

b. 20% in AL (passive in tAL, active in TAL)

c. 5% in DCT and CCD

d. 5% in medullary CD

2. hormonal control of Na reabsorption

a. proximal tubule: AII, NE and volume contraction increase it by increases NHE3 channels

b. AL: ADH increases expression of NKCC2, ROMK, and CLCK2

c. DCT & CCD: aldosterone increases NaCl cotransport

i. aldo sensitive region, esp CCD

ii. without aldo, lose 5% Na (74g) each day ( fatal

v. Na+ excretion regulation

1. aldo

2. GFR (increases will increase Na+ excretion)

3. 3rd factors

a. ANP

i. made in heart atria

ii. released due to increased atrial P and VR

iii. vasodilator ( inhibits AII

iv. increases GFR ( natriuresis and diuresis

v. inhibits Na+ reabsorption in CD

vi. decreases plasma volume by increases capillary permeability to proteins ( favors filtration

vii. net effect: decrease plasma volume and BP

viii. chronic increase in BP: high ANP ( decreased activity of RAS

b. pressure natriuresis and diuresis

i. as BP increases, Na+ excretion rate and urine flow rate increase

ii. ECF volume decreases ( decreases BP

iii. need intact renal capsule to work

iv. decreases Na+ reabsorption in tAL

v. if block NO system, this response is severely attenuated

vi. chronic increase in BP: increased natriuresis and diuresis

4. hypertension can’t be maintained without renal dysfunction

b. DCT cell

i. NaCl cotransporter (NCC) on apical surface

1. activated by aldo

2. inhibited by thiazide diuretics (thiazide sensitive cotransporter – TSC)

3. defective in Gitelman’s syndrome

ii. epithelial Ca2+ channel (ECaC) on apical surface

1. reabsorbs 10% of filtered Ca2+

2. activated by PTH and activated vitamin D3 (and indirectly by thiazides ( decreased intracellular [NaCl] depolarizes cell ( increased electrochemical gradient for Ca2+ entry into cell)

3. Ca2+ inside cell binds calbindin ( moves to basolateral membrane and exits via Na-Ca2+ exchanger and Ca2+ ATPase

iii. always impermeable to water

c. principal cell of CCD

i. epithelial Na channel (ENaC) on apical surface

1. activated by aldo to increase Na+ reabsorption (slow: 1-2h due to increased protein synthesis)

2. inhibited by amilloride diuretics

3. defective in Liddle’s syndrome (looks like hyperaldosterone, but aldo is low)

ii. apical K+ channel

1. entry of Na+ into cell creates large transtubular potential (-30- -60mV) ( draws K+ into lumen

2. concentration gradient helps K+ secretion (high levels in cell due to Na/K ATPase (slowly increased by aldo))

3. slowly activated by aldo

iii. ADH inserts AQP2 into apical membrane (otherwise impermeable to water)

iv. Na delivery rate affects Na reabsorption here: increased delivery due to inhibition of reabsorption proximally will increase reabsorption here and increase K+ secretion

v. mineralocorticoid receptor in cytosol

1. translates to nucleus when binds aldo or cortisol

2. circulating [aldo] = 0.1-1ηM; circulating [cortisol] = 10-1000ηM

a. cortisol doesn’t interfere with aldo’s regulation because it is degraded by 11-β-hydroxysteroid dehydrogenase to cortisone ( low affinity for receptor

b. if missing 11-β-hydroxysteroid dehydrogenase ( hyperaldosteronism

d. K+ balance

i. ingest 100 mEq/d ( excrete 100 mEq/d (mostly by kidneys, some by feces)

ii. reabsorbed

1. 70% in proximal tubule

2. 25% in loop

iii. secretion

1. only 5% enters CCD

2. secreted in aldo-sensitive region (aldo required)

iv. intercalated cell of CD: apical K-H ATPase which normally secretes H+ ions; can reabsorb K+ on a low K+ diet (< 45 mEq/d)

e. intercalated cell of CD

i. secretes H+ ions with normal Western diet

1. aldo stimulates H+ pump in apical membrane ( pH can fall to 4-4.5 here

2. pump can flip to basolateral surface to reabsorb H+ in vegetarian/ alkaline diet ( secretes base

ii. low Na/K ATPase activity

iii. K-H ATPase on apical membrane (activated when low K+ diet)

f. high dose aldosterone

i. mineralocorticoid excape

1. during first few days of high dose, Na+ excretion drops to very low levels despite constant intake

2. retention of Na+ expands ECF (water retained also) ( hypertension

3. expanded ECF decreases COP in peritubular capillaries ( inhibition of Na+ reabsorption in proximal nephron ( causes escape

4. within 4 d, Na+ excretion returns to normal (~150 mEq/d)

ii. K+ and H+ secretion / excretion remain elevated

1. no excape

2. there’s no change in aldo function

3. hypokalemia and alkalosis

g. renin-angiotensin system (RAS) and BP

i. long term effects on BP

ii. stimulation of renin release due to decreased BP

1. increased renal sympathetic nerve activity (activates renal β receptors)

2. decrease pressure in aff. a.

3. decreased distal tubular flow rate (decreased GFR and delivery of NaCl and uptake by macula dense via NKCC2)

iii. cascade from renin activation

1. renin converts antiogensinogen (from liver, high circulating concentration) to angiotensin I (AI) – no activity

2. ACE converts AI ( AII (lots of ACE in endothelium of lungs, some in kidneys and elsewhere)

3. AII acts to increase BP

a. stimulate thirst center (increase drinking)

b. very potent vasoconstriction via AT1 receptors

c. stimulate secretion of ADH from posterior pituitary (increases water reabsorption via V2 receptors)

d. stimulate secretion of aldo from adrenal zona glomerulosa (increase Na+ reabsorption)

i. regulated by K+ in plasma (high ( activates aldo)

ii. regulated by adrenocorticotropic hormone (ACTH): permissive – must be present for AII and PK to work

e. also inhibits renin release

4. ACE degrades kinins (vasodilators) to inactive products

iv. ACE inhibitors (anti-hypertensive)

1. decrease conversion of AI ( AII

2. increase activity of kinins

3. no long term effect on circulating AII because there are other converting enzymes (chymase) in the kidney and heart

4. possible alternative ( AT1 receptor antagonists (losartan)

h.

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