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Renal > Lecture 7: Tubular Fxn 2 > Flashcards

Lecture 7: Tubular Fxn 2 Flashcards

1
Q

Where does bulk reabsorption of Na + anions and water happen?

A

Proximal tubule

2/3!!

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2
Q

Where does fine regulation of NaCl, potassium and water homeostasis occur?

A

DCT

CNT/CD

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3
Q

What gets filtered in the thin descending limb?

A

Water

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4
Q

What gets filtered in the thin AL?

A

NaCl

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5
Q

What gets filtered in the thick AL?

A

25% Na + anions

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6
Q

Where does K secretion occur?

A

CNT/CD principal cell

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7
Q

What gets filtered in the DCT?

A

4-8% Na + anions

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8
Q

What gets filtered in CNT/CD?

A

1-3% Na + anions

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9
Q

What transporter defines the distal convoluted tubule?

A

Na-Cl cotransporter = NCC

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10
Q

Where does expression of DCT’s NCC begin?

A

Downstream of macula densa

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11
Q

Where is the NCC located on the DCT?

A

Apical side

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12
Q

What is the function of the NCC?

A

Reabsorbs 4-8% of filtered Na+

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13
Q

What is Gitelman’s syndrome?

A

Loss of function mutation of NCC

Impaired NCC = salt loss to urine

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14
Q

What drug targets NCC?

A

Thiazides diuretics

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15
Q

How is NCC regulated?

A

NCC is stimulated by low NaCL intake, AngII or sympathetic tone (beta receptors)

Inhibited by high NaCl intake, high potassium diet/ high [K] in plasma

Regulated by WNK kinases

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16
Q

What do CLC-KB (Barton) channels do?

A

Mediate chloride ion exit through basolateral side of cell into blood

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17
Q

What is the driving force for the NCC?

A

Na/K ATPase

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18
Q

How do WNK kinases regulated NCC?

A

Can inhibit NCC so that no sodium or chloride enter/exit cell - no potassium would be brought in

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19
Q

What is the significance of a lack of aquaporins in the DCT?

A

No water reabsorption - appropriate since DCT is part of diluting segment of nephron

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20
Q

What kind of cells line the DCT2/first part of IMCD and the second part of IMCD?

A 
DCT2/first part IMCD =
Principal cells (PC) and intercalated cells (IC)

Second part of IMCD = PC

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21
Q

What what do DCT2, CNT, and CCD function in?

A

Na, K, acid-base regulation

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22
Q

What does outer medullary CD (OMCD) participate in?

A

Acid-base in intercalated cells

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23
Q

What does IMCD participate in?

A

ANP regulates Na

ADH regulates urea

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24
Q

What do principal cells function in from CNT to IMCD?

A

ADH-regulated water permeability and reabsorption

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25
Q

What defines principal cells of DCT2/CNT/CCD?

A

Epithelial Na Channel (ENaC) @ apical side of cell

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26
Q

What drug targets ENaC?

A

Amiloride/triamterene will directly block ENaC

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27
Q

How do ENac and the Na-K ATPase work together in principal cells?

A

Generate lumen negative TEP

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28
Q

What does the lumen negative TEP accomplish?

A

K+ secretion (via ROMK)

H+ secretion (in IC)

Paracellular Cl- reabsorption (via Claudin-4, CL4)

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29
Q

What does aldosterone do in principal cells of DCT2/CNT/CCD?

A

Aldosterone regulates Na and K transport

Aldosterone stimulates:
Na-K ATPase
ENaC
ROMK

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30
Q

What effect does Aldosterone stimulation have in PC of DCT2/CNT/CCD?

A

Increases (by enhancing lumen potential)

Na and Cl reabsorption
K secretion
H secretion (via H ATPase in IC)

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31
Q

What are examples of aldosterone antagonists?

A

Spironolactone

Eplerenone

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32
Q

What happens if there is volume depletion, or high levels of K in plasma?

A

Volume depletion = stimulate AngII =
1) directly stimulate ENac and 2) increase Aldo to bind at Mineralocorticoid receptor and inhibit Nedd4

Both 1) and 2) enhance Na reabsorption

If high K in plasma:
Stimulate Aldo to bind MR and inhibit Nedd4

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33
Q

What does Nedd4 do in principal cells of DCT2/CNT/CCD?

A

Nedd4 regulates ENaC by ubiquitylating and internalizing the receptor to downregulate it

Inhibited by Aldo

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34
Q

What is Liddle’s syndrome?

A

Gain of fxn mutation in ENaC = can’t get ubiquitinated by Nedd4 to internalize it

Results in hyperreabsorption of sodium = mono genetic form of HTN

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35
Q

What are AS channels in principal cells of IMCD?

A

Amiloride-sensitive (AS) sodium channels @ apical end of IMCD cells

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36
Q

What inhibits AS channels?

A

Atrial natriuretic peptide (ANP)

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37
Q

What effect does ANP have?

A

Inhibits AS

Increases GFR

Inhibits renin release

Increases natriuresis

38
Q

How does ANP work?

A

ANP released from heart/atria in response to high volume/distension

Stimulates GPCR = cGMP from GTP inhibits AS

39
Q

What are effects of ENaC inhibition?

A

Increased Na excretion

Increased Cl excretion (since it drives reabsorption normally)

Retains H+ = acidosis

Retains K+ = hyperkalemia

40
Q

What do Type A interacalated cells do?

A

Acid secretion

Bicarbonate reabsorption

41
Q

Where are Type A intercalated cells expressed?

A

DCT2 to initial IMCD

Strongly in OMCD

More cells pop up with acid load

42
Q

What are steps in acid secretion and bicarbonate reabsorption in type A intercalated cells?

A

Formation of H+ (from water) and bicarbonate (from CO2)

Bicarbonate returns to blood via basolateral Cl-HCO3 exchanger called AE1

H+ gets secreted into tubular fluid by H-ATPase and H-K ATPase

Ammonia gets secreted by RhC glycoprotein to form ammonium when combined with secreted H+ - this traps ammonia in urine!

43
Q

What is the primary mechanism to match acid excretion to acid loads?

A

Hydrogen ion excretion as ammonium

44
Q

What do type B intercalated cells do?

A

Bicarbonate secretion and acid retention

45
Q

Where are type B intercalated cells found?

A

CNT to CCD

Concentrated in CCD

More cells pop up with metabolic alkalosis

46
Q

What are steps in bicarbonate secretion and acid retention in type B cells?

A

H+ and bicarbonate formed within cell

H+ returns to blood via basolateral H-ATPase

luminal bicarbonate secretion occurs by Cl-HCO3 exchanger called Pendrin

47
Q

Describe the “plasticity” of Type A and Type B intercalated cells

A

Have ability to convert to type A or B depending on what the body needs

48
Q

What are non A non B intercalated cells involved with?

Where are mainly located?

A

Aldosterone/AngII stimulated chloride reabsorption

Mainly in CNT

49
Q

How do non A non B intercalated cells mediate Cl reabsorption in an acid/base neutral way?

A

Apical Pendrin (Cl/HCO3 exchanger) and H-ATPase

50
Q

Is Pendrin sodium independent or dependent?

A

Sodium independent

51
Q

What are things that bring potassium into cell?

A

Hormones: insulin, beta2 adrenergic agonists

Alkalosis

52
Q

What transporter is responsible for the high ratio of intracellular to extracellular potassium?

A

Na-K ATPase

53
Q

What is a consequence of chronic kidney disease and potassium handling?

A

K+ retention leads to colonic K+ secretion if kidneys start failing

54
Q

How does dietary K+ intake influence potassium reabsorption and secretion?

A

No effect on proximal reabsorption/ loop of Henle reabsorption - implies not regulated there

Dietary K+ regulates transport of potassium DOWNSTREAM of macula densa

55
Q

How do ENaC and Na-K ATPase work together for potassium secretion by principal cells?

A

ENaC and Na-K ATPase generate strong lumen negative TEP, which facilitates K+ secretion into urine

56
Q

By what mechanisms is K+ secreted into urine?

A

ENaC brings sodium into cell, Na/K ATPase exchanges Na for K into cells, which exit via:

Primary:
ROMK

Secondary: BK channel (also in IC cells)

57
Q

How is K+ secretion increased?

A

High plasma potassium, Aldosterone

High luminal Na delivery

58
Q

How is K+ secretion inhibited?

A

Low plasma concentration of potassium or aldosterone (since they inhibit Nedd4)

Aldosterone antagonists

ENaC inhibitors

low luminal Na delivery

59
Q

Increase and inhibition of NCC have what effect on potassium secretion by principal cells?

A

Inhibition of NCC = increase Na delivery for downstream ENaC/ROMK K+ secretion

Stimulation of NCC = decrease Na+ delivery downstream

60
Q

What are examples of factors that increase Na delivery downstream by inhibiting NCC?

A

Thiazides diuretics and Gitelman’s syndrome inhibit NCC => lower BP, hypokalemia

High K+ diet or plasma [K+] inhibit NCC

61
Q

What factors decrease Na+ delivery downstream by stimulating NCC?

A

Low K+ diet or plasma [K+]

Familial hyperkalemic HTN mutations in WNK4/WNK1 kinases

62
Q

Describe the Aldosterone paradox -

Why not kaliuretic (potassium excretion in urine) when triggered by low NaCl diet or volume loss?

A

Co-increase in Ang II enhances NCC activity and limits sodium delivery for K secretion

This means less driving force for K secretion despite having Aldosterone onboard

63
Q

How is NCC a determinant of potassium secretion?

A

Regulates sodium delivery to lumen of cells downstream in DCT2, CNT/CCD

64
Q

Describe potassium reabsorption in type A intercalated cells

A

Luminal H-K ATPase @ apical side of cell reabsorbs K+ from urine

65
Q

What keeps H-K ATPase active in type A intercalated cells for potassium reabsorption?

A

Constitutive activity

Stimulation by low [K+] in plasma/diet

66
Q

What suppresses ADH?

A

Small reduction in plasma osmolality

Large increases in plasma volume/pressure

EtOH

67
Q

What is diabetes insipidus?

A

Impaired ADH responsiveness

68
Q

What factors increase ADH or make it active?

A

Small increase in plasma osmolality

Large reduction in plasma volume/pressure

High circulating AngII levels

69
Q

Where does ADH enhance water permeability?

A

Principal cells of CNT to IMCD

70
Q

Describe steps of ADH enhancing water permeability in principal cells

A

ADH binds basolateral V2 receptor (Gs coupled GPCR = activates PKA)

PKA phosphorylates aquaporin-2 and inserts into apical membrane

ADH also increases aquaporin-2 synthesis

Constitutive basolateral aquaporin-3

71
Q

What are aquaretics?

A

V2 receptor antagonists - primarily excrete water to dilute urine

72
Q

Describe urea recycling in nephron

A

Urea comes in from GFR (about half reabsorbed in PT)

Urea also comes in from vasa recta via UT-A2 transporter

Urea that gets pumped back into medullary interstitium can then recycle back to enter via UT-A2 again

73
Q

What is required for urea recycling?

A

ADH

74
Q

Why is ADH-induced urea transport important?

A

Urea helps maximize concentration of urine

With ADH present, when urea/water travel down CNT/CD, water will get pumped out and urea gets concentrated

75
Q

What are the key structures for generating and maintaining a cortico-medullary osmotic gradient?

A

Medullary loop of Henle

Vasa recta

Both form a countercurrent multiplier system

76
Q

What structure maintains the medullary gradient?

A

Vasa recta act as countercurrent exchangers

77
Q

Describe vasa recta’s permeability to water and solutes

A

Permeable to NaCl, urea and water:

Water diffuses out of descending vessels and bypasses the medulla

Solutes move out of ascending vessels and recirculate in medulla

78
Q

How can the gradient in the vasa recta get washed out?

A

Large blood flow

Osmotic diuretics - retain water in tubules and in descending vasa recta (traps water and drags it down medulla which messes up solute concentration building down there)

79
Q

What does intact urine concentration require?

A

ADH

V2 receptor

Aquaporin-2

80
Q

Describe diabetes insipidus

A

(1) central -
Due to impaired generation of ADH; respond to exogenous ADH

(2) nephrogenic -
Sometimes inherited (mutations in V2 receptor or AQP-2); more frequently acquired (ex: lithium impairs urine concentrating ability)
81
Q

What is desmopressin?

A

Exogenous ADH

82
Q

Correlate each with distal nephron segment (DCT, CNT/CD) and cell type:

A) sodium reabsorption by a channel
B) sodium reabsorption by a channel regulated by ANP
C) NaCl reabsorption by a cotransporter
D) K reabsorption, naming the apical transporter

A

A) Principle cells in DCT2/CNT > CCD
Epithelial Na Channel (ENaC)

B) Principle cells of IMCD = Amiloride-sensitive (AS) channel

C) DCT = Na-Cl cotransporter (NCC)

D) OMCD&raquo_space; DCT2 to IMCD = H-K ATPase in type A intercalated cells

83
Q

Correlate each of the following with DCT, CNT/CD and cell type:

H) bicarbonate secretion, naming apical transporter and the clinical condition in which this transport is important
I) water reabsorption in the presence of ADH, naming the channel
J) Urea reabsorption, naming the transporter and the hormone that increases its activity

A

H) CNT/CCD (Type B cells and non A non B cells) = Pendrin - metabolic alkalosis

I) CNT/CD (principal cells) = Aquaporin2

J) IMCD cells in CD = UT transporter; stimulated by ADH

84
Q

Identify the transporters that are

(A) inhibited by thiazide diuretics

(B) inhibited by triamterene and amiloride

A

A) NCC

B) ENaC

85
Q

For aldosterone:

(A) list two factors that stimulate secretion

(B) Name aldosterone receptor

(C) explain how it affects Na and K transport in CNT/CCD - identifying transporters and enzymes that are stimulated by aldosterone

(D) name a drug that antagonizes action of aldosterone

A

(A) AngII (also from volume depletion) or high plasma [K+]
(B) Mineralocorticoid receptor (MR)
(D) spironolactone, eplerenone

(C) Aldo stimulates MR and inhibits Nedd4. Aldo stimulates Na-K ATPase, ENaC and ROMK, resulting in increases of: Na reabsorption, K secretion, Cl reabsorption, H secretion (in intercalated cells)

86
Q

Name two solutes secreted by type A intercalated cells (ICs) and one solute reabsorbed by them

Name primary mechanism that matches acid excretion to acid load

A 
Secreted = H+, NH3
Reabsorbed = bicarbonate

Primary mechanism that matches excretion to load = hydrogen ion excretion as ammonium

87
Q

Name two apical transporters in non-A non-B cells

Identify the main function of these cells

A

Apical transporters =
H-ATPase
Pendrin (HCO3 secretion, Cl reabsorption)

Function: CL- reabsorption in acid base neutral way

88
Q

Given a typical dietary intake of 100 mEq of potassium/day, predict urinary excretion

Name a hormone that regulates potassium excretion and explain relationship between CKD, hyperkalemia and colonic potassium secretion

A

approx. 92 mEq excreted

CKD = potassium retention leads to colonic secretion in order to maintain balance

Aldosterone regulates potassium secretion

89
Q

Describe the overall potassium transport in the distal nephron, naming the major cell types and tubular segments that are most responsible

A

Secretion in DCT, CNT and CCD = principal cells and ROMK/BK channels
*BK channels also in IC cells

Reabsorption in OMCD = type A IC cells via H-K ATPase

90
Q

Predict and briefly explain the effect of amiloride and thiazide diuretics on potassium secretion

A

Thiazides diuretics =
Inhibition of NCC = less Na delivery = less K secretion = hypokalemia

Amiloride/triamterene = block ENaC = less K secretion via ROMK = hypokalemia

Renal (17 decks)

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