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UNL / Management / MNGT 213 / What are the three key processes in and around tubules?

What are the three key processes in and around tubules?

What are the three key processes in and around tubules?

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*words highlighted in red are fill-in-the-blank answers


What are the three key processes in and around tubules?



~January 23rd, 2017

Three key processes in and around tubules

★ Filtration - selective removal; blood → lumen of nephron at renal capsule. ★ Reabsorption - material returned to blood from nephron lumen.

★ Secretion - material enters nephron lumen after renal capsule.

--note difference between these terms and “transport”

Specific functions/events in parts of the nephron

A. Filtration in ​glomerulus

--blood enters glomerular capillaries (capillaries are very leaky)

★ Fenestra: large pore that creates the leaky membrane.

--pushed through membranes into Bowman’s capsule (nephron) by blood pressure


What is the role of renal system in regulating ph?



--all contents of plasma enter except large molecules (ex: lipoproteins, proteins, cell remains) = filtration

--20% of blood filtered per each pass through nephron

--initially, filtrate is iso-osmotic with blood

--volume of filtrate/unit of time = GFR = glomerular filtration rate

-normal GFR: 115-125 mL/min = 180 liters/day

-total blood volume = 5.5 liters

-entire blood volume filtered every 45 minutes!

-1-2 liters urine/day; minimally 400 mL = obligatory water loss

B. Proximal Convoluted Tubule​ (in cortex of kidney) Don't forget about the age old question of How is the cns built?

--entering filtrate is 0.3 Osm (iso-osmotic with surrounding tissue)


What are the effects of aldosterone?



--65% of original filtrate volume leaves nephron = reabsorption 

1) All ​glucose and amino acids​ reabsorbed

​--by secondary active cotransport with Na+ from lumen

2) 65% of NaCl​ reabsorbed

​--Na+/K+ pump on basolateral side sets up Na+ gradient

--Na+ entry through channels from apical = lumen side of nephron

--also cotransport of Na+ with glucose

--Cl- follows electrical gradient from Na+ leaving

3) 65% of water​ reabsorption - osmotic gradient set up due to ions leaving lumen; water follows

​Filtrate iso-osmotic at beginning and end of proximal convoluted tubule

4) Some materials ​secreted​ by active transport If you want to learn more check out What are the major types of organic molecules?

​--drugs (ex:penicillin), saccharine, bile salts

--transporter required for each compound

5) Regulated reabsorption of ​bicarbonate and secretion of H+​ -​-regulates blood pH --getting rid of acidity

C. Descending limb of Loop of Henle (DLOH)

​--in medulla of kidney (hypertonic)

--water reabsorption by osmosis → from low salt concentration to high salt concentration --DLOH permeable to water but not ions

--filtrate concentrated (volume decreases by 20%)

--filtrete 300 mOsm at top of loop becomes >1200 mOsm at bottom

D. Ascending Loop of Henle (ALOH)

​--filtrate about 1400 mOsm as it enteres ALOH (about 85% of water has been removed) --ALOH impermeable to water (tight junctions); no water channels

*words highlighted in red are fill-in-the-blank answers

-no water loss on the “way up”

--upper regions of ALOH thicker, contains Na+/K+ pumps

--active transport of Na+ by pumps, out basolateral side of tubule cell into ECF

--concentration of tubule cells of nephron is lowered

--Na+ enters tubule cell from hyperosmotic filtrate (lumen) If you want to learn more check out What is the difference between introns and exons?

--secondary active transport of Cl- into tubule cell from lumen (passive trans-channel) --Cl- out basolateral side; bollow Na+ (electrostatic)

--overall, NaCl moves from filtrate (tubule lumen) into cell and out into interstitial fluid --at top of ALOH, filtrate is 100-200 mOsm (hypo-osmotic)

Summary of ALOH 

--NaCl removed

--Water retained

--Filtrate hyperosmotic → hypo-osmotic

--some reabsorbed NaCl trapped in medulla of kidney;creates hypertonicity of medulla E. Distal Convoluted tubule Don't forget about the age old question of What makes price elasticity of demand very useful today?

​--Additional reabsorption of Na+ and Cl-, secretion of K+ (regulated​)

-filtrate hypo-osmotic

--Main site where Na+/K+ concentration in filtrate is regulated 

F. Collecting Duct (CD)

--iso-osmotic filtrate descends back into medulla of kidney

--CD impermeable to salt

--osmosis through aquaporins (water channels) (regulated​)

--main site where H2O reabsorption is regulated

--urine very hypertonic - but isosmotic with tissue in medulla (1,200 mOsm) Don't forget about the age old question of What is the #1 reason why new products fail?

--some urea leaves collecting duct; facilitated diffusion (via transporter) -- contributes to hyperosmotic environment in medulla

Factors creating and maintaining hyperosmolarity of medulla

--Hypertonicity of medulla key for water reabsorption in Descending Loop of Henle (DLOH) 1) Removal of NaCl from lumen of nephrons into interstitial fluid of kidney -​Some NaCl is removed from the filtrate and retained in the medullar increasing osmolarity --Rate influenced by close proximity and interaction between ALOH & DLOH Don't forget about the age old question of What happens if the numbers are not whole numbers?

--Gives rise to _________ (read in book)

Self-reinforcing system operating by positive feedback to increase removal of NaCl (and water from lumen:

--Removal of NaCl from lumen of ALOH causes increased removal of water from the DLOH; --This increases concentration of NaCl arriving at the pumps in ALOH.

--Which, in turn, causes more removal of NaCl, and so on--

As described below, although both NaCl and water are removed from filtrate into the interstitial fluid, water is subsequently removed to a greater than NaCl to maintain the hypertonicity of the medulla 2) Vasa Recta

--​Network of blood vessels

--Arrangement (direction of blood flow; hairpin) and charge of blood vessels in Vasa Recta --Removes water, but retains NaCl in medulla

3) Urea Reabsorption

--​Some urea removed from collecting duct via urea transporters

Urea - important osmolyte -- for maintaining hyperosmolality of medulla of kidney.

*words highlighted in red are fill-in-the-blank answers

~January 25th, 2017

Regulatory​ aspects of renal function

1) pH control in (PCT)

--H+ secretion

--bicarbonate reabsorption

--production of new bicarbonate

Background on Buffers and pH regulation

--​ph measure of acidity/alkalinity

★ pH = -log [H+] [ ] = concentration

--range 0-1; 0 = very acidic; 14 = very alkaline; log scale

--pH of various bodily fluids --- typically kept within a narrow range by a variety of factors; one of most important - buffers

★ Buffer - system of molecules and ions that acts to prevent changes in pH (ex: weak acid and weak base).

--Most important buffer in body fluids (ex: blood plasma) in bicarbonate

--Consists of bicarbonate ion (HCO3- : weak base) and carbonic acid (H2CO3 : weak acid); interact as follow:

HCO3- + H+​ <-----> CO2 + H2O (H+ is the key player)

--Reversible reaction​; direction depends upon concentration of reactants and products--termed Mass Action

--Acids (ex: H+ from lactic acid produced by metabolism) neutralized; react with bicarbonate ions --Also H+ excreted -- prevents the pH from dropping significantly

--Excess base neutralized by H+; more H+ produced from H2CO3

--Other important buffer in kidney : Ammonia and phosphate; pH of urine normally acidic (acid products of metabolism excreted); Ammonia and phosphate buffers prevent pH of urine from becoming too acidic (< 4.5), when a lot of acid is excreted.

The main problem in pH regulation in body fluids is the neutralization of acid products of metabolism

Aerobic metabolism - produces CO2 which produces carbonic acid when dissolved in water. Anaerobic metabolism - produces a variety of acids such as lactic acid.

--These acid products must be continuously neutralized and H+ excreted

--In addition, a variety of diseases can either raise or lower body pH

Three important regulators of body (mainly blood) pH:

(1) Buffers (2) Renal System (3) Respiratory System

Integration of renal and nervous system

(1) Buffers ​regulate pH by neutralizing acid and bases especially acids produced by metabolism --but only limited amount of acids or bases can be neutralized

 (2) Renal System​ regulates pH by

 (a)Excreting components of bicarbonate buffer system

(i) Excreting (H+) -- increases blood pH or…

(ii) Excreting (HCO3-) -- decreases blood pH

 (b) producing new bicarbonate (from CO2 and water)

 (3) Respiratory System​ regulates pH by removal of CO2 by breathing

--increased breathing (hyperventilation) causes removal of CO2 -- raises pH of body fluids --Respiratory system is a more important short-term regulator of body pH

Role of renal system in regulating pH

Under normal conditions; body pH within normal range; acids produced by normal metabolism

*words highlighted in red are fill-in-the-blank answers

Two important points:

(1) Nearly all bicarbonate reabsorbed (by PCT); much H+ excreted (secreted by PCT); both of these help to keep blood pH constant when H+ continuously produced by metabolism

(2) New bicarbonate also produced (from PCT--tubule cell) --neutralizes new acids Productions of new bicarbonate

(1) Standard Conditions

--CO2 produced by cell metabolism can be converted into bicarbonate by the enzyme carbonic anhydrase (CA) within the tubule cell --new bicarbonate produced

CO2 + H2O ----------> H2CO3 ----------> HCO3- + H+ <--excreted (secreted)  CA ​ ^ to body via transporter

(2) Failsafe Mechanism

--New bicarbonate (and ammonia) are produced from the amino acid glutamine; both neutralize H+ --operates when pH becomes very acidic due to unusual conditions (ex: diabetes, excess bicarbonate loss due to excessive diarrhea)

--other compounds in blood can neutralize acids -- ex: hemoglobin (important buffer) Bicarbonate reabsorption requires “​shuttle​”

--HCO3- cannot be directly reabsorbed (too polar) -- only transporter can pass HCO3- across membrane

--H+ and HCO3- combine to form compounds (CO2 and H2O) that can cross the membrane --catalyzed by the enzyme carbonic anhydrase (CA), attached to the luminal side of tubule cell --HCO3- and H+ then regenerated within the tubule cell by CA --enzyme reaction is reversible Net effect - retention of all bicarbonate; excretion of H+.

--shuttle important in physiology

Summary and synthesis: pH regulation by kidney and lungs :

Standard conditions (pH normal) 

--nearly all bicarbonate reabsorbed; some new bicarbonate produced by kidney; excetion of H+; urine slightly acidic

--Lungs: normal rate of breathing -- CO2 expiration matches CO2 production by metabolism Response to acidosis 

--decreased reabsorption of bicarbonate; decreased excretion of H+ (decreased secretion of H+ into lumen)

--Lungs: decreased rate of breathing (hypoventilation)

--ex: interaction between organs systems alike

*words highlighted in red are fill-in-the-blank answers

~January 27th, 2017

Other regulatory aspects of Kidney:

Regulated reabsorption/secretion of Na+, K+, H2O; occurs at later part of nephron as expected for fine-control mechanism

(1) Reabsorption of Na+ (DCT)

--90% total reabsorption of Na+ in PCT and ALOH but unregulated

-8% additional unregulated reabsorption in DCT

-98% reabsorption of Na+ is unregulated 

--2% regulated absorption by hormone aldosterone; (increases # of pumps/transporters) -- 0% - 2% reabsorption depending on Na+ concentration of body fluids

--In DCT -distal convoluted tubule

-2% seems small, but = 30 g!; because large volume of filtrate

-increased reabsorption of Na+ coupled with increased secretion of K+ (or H+) --to maintain electrical balance

★ Aldosterone - steroid hormone.

 (2) K+ secretion -- not reabsorption - regulated in DCT

--​90% of total reabsorption in PCT -- unregulated

-remaining 10% is reabsorbed in DCT if no aldosterone

-increased K+ secretion due to aldosterone (“undoes” the 10% normal reabsorption in DCT) -0-10% reabsorption “undone” depending upon concentration of K+ in body fluids

-increased secretion of K+/H+ coupled to increased reabsorption of Na+

(3) Water ​absorption in CD

--upregulated reabsorption in PCT, DLOH

--CD main site of regulated reabsorption

--Antidiuretic hormone (ADH)

Diabetes insipidus - tasteless; producing large volumes of water.

--caused by malfunctioning ADH or receptor; reduced reabsorption of water; up to 5-10 L of dilute urine/day produced

--large urine volume + increased thirst mimics symptoms of diabetes mellitus (must no elevated glucose concentration in urine)

-diabetes = siphon = large urine volumes

(4) Blood flow to glomerulus

--constriction/dilation of afferent arteriole

--regulates amount of blood entering glomerulos

--sympathetic NS (fight or flight syndrome) → regulated by nervous & endocrine systems

--constriction of blood flow -----> (1) diversion of blood to muscles and heart -- for action &

(2) also conserves blood volume to important organs (ex: during cardiovascular shock)

Integration of nervous, renal, and cardiovascular systems

--renal autoregulation (read in book)

Hormonal Mechanisms involved in regulation -- more details

ADH (anti-diuretic hormone)

Diuresis - increased urine volume.

ADH = hormone that reduces urine volume (by increasing H2O reabsorption)

Neurohormone (neuropeptide) - produced by modified neurons of hypothalamus (neurosecretory cells).

--mainly affects collecting duct

--main site where water reabsorption is under physiological control (ex: regulated)

*words highlighted in red are fill-in-the-blank answers

--increases production and transfer of aquaporins to luminal membrane collecting duct --increases water reabsorption

--without ADH reduced rate of osmosis within ½ hour; loss of water channels (peptide hormone act quickly)

--ADH release triggered by osmoreceptors in hypothalamic

--due to increased plasma osmolarity (ex: due to dehydration)

--ADH reduced when plasma osmolarity drops (ex: when a lot of water is drunk)

--effects of ADH is inhibited by some drugs such as alcohol, caffeine--diuretics = substances which causes increased urine volume

**ADH primarily regulates t​ otal body water.​ Water can easily move in/out of cell, interstitial fluid, and blood.

 --Aldosterone

--steroid -- Mineralocorticoid -- produced in adrenal cortex

**Aldosterone primarily regulates Na+, blood plasma volume, and blood pressure Direct effect - regulates Na+/K+ concentration in plasma (plasma volume).

Indirect effect - regulates H2O concentration of blood plasma (the liquid part of blood). **Main regulator of aldosterone release -- reduced blood volume/blood pressure

--strong relationship between Na+ concentration in blood and blood volume; 90% of osmolytes outside of cell = Na+ (increase in Na+ = increase in H2O = increase in blood volume) Effects of aldosterone:

(1) Production and insertion of Na+ channels

(2) Production and insertion of Na+/K+ ATPase (pumps)

--Lower DCT + upper collecting duct; also intestine, sweat glands

--Increased NaCl reabsorption (remains in blood plasma); increased water reabsorption results (remains in plasma because of increased NaCl in plasma) = increased blood pressure  --Aldosterone regulates blood volume/blood pressure (but not total body water) as well as Na+, K+ concentration

 (3) Production and insertion of K+ channels

--increased K+ secretion into DCT

Summary

ADH - regulates water absorption only

--​faster than aldosterone (minutes vs. hours)

--primarily regulates total body water (inside and outside of cells)

Aldosterone -

​--regulates: Na+/K+ concentration directly; H2O concentration indirectly

--primarily regulator of plasma volume; important regulator of blood pressure

Secretion of aldosterone is complex

--​increase in K+ directly stimulates aldosterone release from adrenal glands

--decrease in Na+ causes decrease in blood volume which indirectly stimulates secretion of aldosterone

--Aldosterone stimulation via renin-angiotensin system

Renin - enzyme from kidney juxtaglomerular apparatus

--groups of cells near top of ascending limb, LOH

--Renin, together with another enzyme, converts and inactive hormone (angiotensinogen) to an active hormone (angiotensin). Angiotensin regulates release of aldosterone (hormonal/enzyme amplification) ACE - Angiotensin converting enzyme (in lungs).

Renin release triggered by:

*words highlighted in red are fill-in-the-blank answers

Baroreceptors - measure pressure; in juxtaglomerular apparatus.

--low blood pressure or low flow stimulates juxtaglomerular apparatus → renin released --Baroreceptors in carotid sinus of heart; direct neural input to juxtaglomerular cells; triggered by low blood pressure

Another good example of physiological integration

--if no aldosterone, 35 g of NaCl lost per day (10 g normally)

Hormonal regulation of salt and water reabsorption is much more complex than indicated in these notes or in the textbook ​- general principle -- the more important a physiological trait, the more complex the regulation.

A few additional examples illustrating this complexity:

--ADH and aldosterone affect the secretion of each other -- coordination

--Each of these hormones has additional effects -- ex: contraction of arterioles (angiotensin); influence thirst --Angiotensin (which controls release of aldosterone), also has important effects - constricts arterioles --Aldosterone release also directly influenced by salt concentration - but not as important as regulation by blood pressure

**Other hormones are involved:

--atrial natriuretic peptide (ANP)

--produced in atria of heart

--antagonizes effect of aldosterone;; inhibits ADH release

--released when atria stretch due to increased blood pressure

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