Solute and water transport along the nephron: Tubular function (berne Ch. 33)

Question 1

The formation of urine involves three basic processes:

Answer 1

1. ultrafiltration of plasma by the glomerulus
2. reabsorption of water and solutes from the ultrafiltrate
3. secretion of selected solutes into tubular fluid

Question 2

These mediate the reabsorption and secretion of solutes and water in the kidneys

Answer 2

Transport proteins in cell membranes of the nephron

Question 3

The key element in proximal tubule reabsorption (transport mechanism)

Answer 3

Na+,K+-ATPase in the basolateral membrane

Question 4

Na+ reabsorption in the 1st HALF of the PROXIMAL tubule:

Answer 4

Na+ reabsorption in the 1st HALF of the PROXIMAL tubule:
Nais reabsorbed primarily with bicarbonate (HCO3) and a number of other solutes (e.g., glucose, amino acids, Pi, lactate)

Question 5

Na+ reabsorption in the 2nd HALF of the PROXIMAL tubule:

Answer 5

Na+ is reabsorbed mainly with Cl-

Question 6

In the first half of the proximal tubule, Nauptake into the cell is coupled with _____

Answer 6

H or organic solutes

• • Specific transport proteins mediate entry of Nainto the cell across the apical membrane. For example, the Na-Hantiporter (NHE3) couples entry of Nawith extrusion of Hfrom the cell
• *Naalso enters proximal cells via several symporter mechanisms, including Na-glucose, Na–amino acid, Na-Pi, and Na-lactate

Question 7

In the first half of the proximal tubule, the glucose and other organic solutes that enter the cell with Naleave the cell across the basolateral membrane via what transport mechanism?

Answer 7

Passive transport mechanisms

**Any Nathat enters the cell across the apical membrane leaves the cell and enters the blood via Na,K-ATPase

Question 8

In the first half of the proximal tubule, what provides the driving force for the passive reabsorption of water by osmosis?

Answer 8

Transtubular osmotic gradient (i.e., the osmolality of the interstitial fluid bathing the basolateral side of the cells is higher than the osmolality of tubule fluid)
**Established by the reabsorption of NaHCO3 and Na–organic solutes

Question 9

The filtered amount of any substance is calculated by ______

Answer 9

Multiplying the concentration of that substance in the ultrafiltrate by the glomerular filtration rate (GFR)
**[Na]Ultrafiltrate (140 mEq/L) X GFR (180 L/day) = 25,200 mEq/day

Question 10

In the second half of the proximal tubule, Na is mainly reabsorbed with Cl through the (a) transcellular (b) paracellular pathway

Answer 10

Both

Question 11

Mechanism of transcellular Na reabsorption in the second half of the proximal tubule:

Answer 11

The uptake of Na and Cl from the tubule fluid into the cell constitutes what transport mechanisms?
Na-Hantiporter and one or more Cl-anion antiporters
**Naleaves the cell via Na,K-ATPase, and Cl leaves the cell and enters the blood via a K-Cl symporter in the basolateral membrane

Question 12

Paracellular NaCl reabsorption occurs in the second half of the proximal tubule because of ____

Answer 12

The high [Cl] concentration gradient in the tubule fluid of the second half of the proximal tubule due to the preferential reabsorption of Na with HCO3 and organic solutes in the first half of the proximal tubule

• *This concentration gradient favors diffusion of Cl from the tubular lumen across the tight junctions into the lateral intercellular space
• • Movement of the negatively charged Cl results in the tubular fluid becoming positively charged relative to blood. This positive transepithelial voltage causes the diffusion of positively charged Na out of the tubular fluid across the tight junction into blood.

Question 13

Na transport processes in the first half of the proximal tubule:

Answer 13

Operation of the Na-Hantiporter (NHE3) in the apical membrane and the Na,K-ATPase and
HCO3 transporters, including the Cl-HCO3 antiporter (AE2) and the 1Na-3HCO3 symporter (NBC1) in the basolateral membrane mediate reabsorption of NaHCO3. Carbon dioxide and water combine inside the cells to form Hand HCO3 in a reaction facilitated by the enzyme carbonic anhydrase (CA).

Question 14

Some glucose is also reabsorbed in the second half of the proximal tubule by a mechanism similar to first half of the proximal tubule. What is the difference between the transporter found in the first half of the proximal tubule (SGLT2) and the one found in the second half of the tubule (SGLT1)?

Answer 14

The Na-glucose symporter (SGLT1 gene) transports 2Na with one glucose and has higher affinity and lower capacity than the Na-glucose symporter in the first part of the proximal tubule
**In addition, glucose exits the cell across the basolateral membrane via GLUT1 rather than via GLUT2 as in the first part of the proximal tubule

Question 15

Overall, only a small percentage of proteins cross the glomerulus and enter Bowman’s space. What is the concentration of proteins in the glomerular ultrafiltrate?

Answer 15

40 mg/L

Question 16

Amount of filtered protein per day

Answer 16

Filtered protein = GFR X [Protein] in the ultrafiltrate

** Filtered protein = 180 L/day X 40 mg/L = 7.2 g/day

Question 17

Mechanism of protein uptake into the proximal tubule cells

Answer 17

Endocytosis

• *Once the proteins and peptides are inside the cell, enzymes digest them into their constituent amino acids, which then leave the cell across the basolateral membrane by transport proteins and are returned to the blood
• *mediated by apical membrane proteins that specifically bind luminal proteins and peptides. These peptides, called multiligand endocytic receptors, can bind a wide range of peptides and proteins and thereby mediate their endocytosis

Question 18

Mechanism of organic anion (OA) secretion in the proximal tubule:
Organic anions from the blood are taken up into the cell, across the basolateral membrane, against their chemical gradient through what transport mechanism?

Answer 18

OA–a-KG antiporter mechanisms (OAT1, and OAT3)
This
secretory pathway has a maximum transport rate and low specificity
**a-ketoglutarate (a-KG) accumulates inside the cells via metabolism of glutamate, and through Na–a-KG symporter (i.e., a Na-dicarboxylate transporter [NaDC]) also present in the basolateral membrane

Question 19

Mechanism of organic anion (OA) secretion in the proximal tubule:
Organic anions from the blood are taken up into the cell, across the basolateral membrane through OA–a-KG antiporter mechanism. What mechanisms are responsible for transporting OA across the luminal membrane into tubular fluid?

Answer 19

OAs are transported across the apical membrane by OAT4, which is electrogenic, and by MRP2 (multidrug resistance–associated protein 2)

Question 20

Mechanism of organic cation (OC) secretion in the proximal tubule:
Organic cations from the blood are taken up into the cell, across the basolateral membrane, through what transport mechanisms?

Answer 20

Passive diffusion, OCT1, OCT2, and OCT3
**Uptake by all four mechanisms is driven by the magnitude of the cell’s negative potential difference across the basolateral membrane

Question 21

Mechanism of organic cation (OC) secretion in the proximal tubule:
Organic anions from the blood are taken up into the cell, across the basolateral membrane through passive diffusion, OCT1, OCT2, and OCT3. What mechanisms are responsible for transporting OC across the luminal membrane into tubular fluid?

Answer 21

OC-H antiporters (MATEs) and MDR1 (a.k.a. P-glycoprotein)

• • These transport mechanisms mediating secretion of OCs are nonspecific
• *Secretion of OCs is stimulated by protein kinase A and C and by testosterone

Question 22

True or false

Henle’s loop reabsorbs approximately 65% of the filtered NaCl and 45% of the filtered water

Answer 22

False

• *majority of reabsorption happens at the proximal tubule
• *Henle’s loop reabsorbs approximately 25% of the filtered NaCl and 15% of the filtered water

Question 23

Where does the reabsorption of NaCl in the loop of Henle occur?

Answer 23

Thin ascending and thick ascending limbs

• *The descending thin limb does not reabsorb NaCl
• *Water reabsorption occurs exclusively in the descending thin limb via AQP1 water channels

Question 24

Thin ascending limb reabsorbs NaCl through: ____; thick ascending limb reabsorbs NaCl through: ____

Answer 24

Passive mechanism; Na,K-ATPase pump in the basolateral membrane

Question 25

Transport mechanism for reabsorption of NaCl in the thick ascending limb of the loop of Henle:
Movement of Na from the tubule fluid into the cell is mediated by what transport mechanism?

Answer 25

1Na-1K-2Cl symporter (NKCC2), Na-H antiporter and paracellular transport of Na along with other cations such K, Mg and Ca.

• *Increased NaCl transport by the thick ascending limb increases the magnitude of the positive voltage in the lumen, and this voltage is an important driving force for the reabsorption of several cations across the paracellular pathway
• *thick ascending limb produces a fluid that is dilute relative to plasma thus the ascending thick limb of Henle’s loop is called the “diluting segment”

Question 26

Set of autosomal recessive genetic diseases characterized by hypokalemia, metabolic alkalosis and hyperaldosteronism. Inactivating mutations in the gene coding for the 1Na-1K-2Clsymporter (NKCC2 or SLC12A1), the apical Kchannel (KCNJ1 or ROMK) or the basolateral Cl channel (ClCNKB) decrease both NaCl reabsorption and K reabsorption by the ascending thick limb, which in turn causes hypokalemia and a decrease in ECF volume. The fall in ECF volume stimulates aldosterone secretion, which in turn stimulates NaCl reabsorption and H secretion by the distal tubule and collecting duct

Answer 26

Bartter’s syndrome

Question 27

The distal tubule and collecting duct reabsorb approximately how many percent of the filtered NaCl?

Answer 27

8%

Question 28

True or false

The initial segment of the distal tubule (early distal tubule) reabsorbs Na, Cl and Ca and is impermeable to water

Answer 28

True

• *Entry of NaCl into the cell across the apical membrane is mediated by an Na-Cl symporter
• *Na leaves the cell via the action of Na,K-ATPase, and Cl leaves the cell via diffusion through Cl channels

Question 29

The last segment of the distal tubule (late distal tubule) and the collecting duct are composed of two cell types:

Answer 29

Principal cells and intercalated cells

Question 30

Principal cells
Reabsorb:
Secretes:

Answer 30

Reabsorb: NaCl and water
Secretes: K

Question 31

K is secreted from blood into tubular fluid by principal cells in two steps:

Answer 31

1. First, uptake of K across the basolateral membrane is mediated by the action of Na,K-ATPase
2. K leaves the cell via passive diffusion (electrochemical gradient)

Question 32

Intercalated cells
Reabsorb:
Secretes:

Answer 32

Reabsorb: K by the operation of H, K-ATPase in the apical surface of cells
Secretes: Hor HCO3

Question 33

Mechanism of Na uptake from tubule fluid across the luminal surface of INTERCALATED CELLS of late distal tubule:

Na enters the cell across the apical membrane via what transport mechanism?

Answer 33

Diffusion through epithelial Na-selective channels (ENaCs) in the apical membrane

Question 34

What mechanism mediates Cl reabsorption in the distal tubule and collecting duct?

Answer 34

Reabsorption of Nagenerates a negative luminal voltage across the late distal tubule and collecting duct, which provides the driving force for reabsorption of Clacross the PARACELLULAR PATHWAY

Question 35

A variable amount of water is reabsorbed across principal cells in the late distal tubule and collecting duct. Water reabsorption is mediated by what mechanism?

Answer 35

1. AQP2 water channel located in the apical plasma membrane
2. AQP3 and AQP4 located in the basolateral membrane of principal cells
   * *In the presence of antidiuretic hormone (ADH)

Question 36

Quantitatively the most important hormones that regulate NaCl reabsorption and thereby urinary NaCl excretion

Answer 36

Angiotensin II, aldosterone, catecholamines, natriuretic peptides, and uroguanylin

Question 37

The only major hormone that directly regulates the amount of water excreted by the kidneys

Answer 37

Antidiuretic hormone (ADH)

Question 38

Angiotensin II has a potent stimulatory effect on reabsorption of NaCl and water in the proximal tubule. It has also been shown to stimulate reabsorption of Na in the thick ascending limb of Henle’s loop, as well as the distal tubule and collecting duct. What stimulate the production of angiotensin II?

Answer 38

A decrease in extracellular fluid (ECF) volume activates the reninangiotensin-aldosterone system thereby increasing the plasma concentration of angiotensin II

Question 39

Aldosterone is synthesized by what structure?

Answer 39

Glomerulosa cells of the adrenal cortex

Question 40

Aldosterone
Structures stimulated (nephron):
Stimulation of reabsorption:
Stimulation of secretion:

Answer 40

Structures stimulated (nephron): thick ascending limb of the loop of Henle, distal tubule and collecting duct
Stimulation of reabsorption: NaCl reabsorption in the distal tubule and collecting duct
Stimulation of secretion: K secretion in the distal tubule and collecting duct

Question 41

In the EARLY DISTAL TUBULE, NaCl absorption is stimulated by aldosterone by _____

Answer 41

Increasing the abundance of the Na-Cl symporter

Question 42

Aldosterone enhances reabsorption of NaCl across PRINCIPAL CELLS in the DISTAL TUBULE and COLLECTING DUCT by four mechanisms:

Answer 42

1. Increasing the amount of Na,K-ATPase in the basolateral membrane
2. Increasing expression of the sodium channel (ENaC) in the apical cell membrane
3. Elevating Sgk1 (serum glucocorticoid-stimulated kinase) levels, which also increases the expression of ENaC in the apical cell membrane
4. Stimulating CAP1 (channel-activating protease, also called “prostatin”), a serine protease that directly activates ENaCs by proteolysis
   * * The increase in reabsorption of Nagenerates a negative transepithelial luminal voltage across the distal tubule and collecting duct. This negative voltage in the lumen provides the electrochemical driving force for reabsorption of Clacross the tight junctions (paracellular pathway) in the distal tubule and collecting duct

Question 43

Secretion of aldosterone
Stimulated by:
Inhibited by:

Answer 43

Stimulated by: Angiotensin II and hyperkalemia

Inhibited by: Hypokalemia and natriuretic peptides

Question 44

ANP and BNP (a) reduce (b) increase blood pressure by (a) decreasing (b) increasing total peripheral resistance and enhancing urinary excretion of NaCl and water

Answer 44

a. reduce; a. decreasing
* * These hormones inhibit reabsorption of NaCl by the medullary portion of the collecting duct and inhibit ADH-stimulated water reabsorption across the collecting duct

Question 45

A 32–amino acid hormone that differs from ANP by the addition of four amino acids to the amino-terminus

Answer 45

Urodilatin

** Urodilatin is secreted by the distal tubule and collecting duct and is not present in the systemic circulation

Question 46

IN THE CLINIC
A rare genetic disorder characterized by an increase in blood pressure secondary to an increase in ECF volume. It is caused by activating mutations in either the
B or ysubunit of the epithelial Nachannel (ENaC)

Answer 46

Liddle’s syndrome

Question 47

IN THE CLINIC
Some individuals with expanded ECF volume and elevated blood pressure are treated with drugs that inhibit angiotensin-converting enzyme. The inhibition of ACE blocks the degradation of angiotensin I to angiotensin II and thereby lowers plasma angiotensin II levels. The decline in plasma angiotensin II concentration has three effects:

Answer 47

1. Reabsorption of NaCl and water by the nephron (especially the proximal tubule) falls
2. Aldosterone secretion decreases,thus reducing reabsorption of NaCl in the thick ascending limb, distal tubule, and collecting duct
3. A reduction in its concentration permits the systemic arterioles to dilate and thereby lower arterial blood pressure

Question 48

The natriuretic response of the kidneys to an NaCl load is more pronounced when given orally than when delivered intravenously because ____

Answer 48

Oral administration of NaCl causes the secretion of uroguanylin and guanylin

Question 49

It is the most important hormone that regulates reabsorption of water in the kidneys. This hormone is secreted by the posterior pituitary gland in response to an increase in plasma osmolality (1% or more) or a decrease in ECF volume (>5% to 10% of normal)

Answer 49

ADH