Disorders of tubular function.txt

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yuiness
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39095
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Disorders of tubular function.txt
Updated:
2010-10-03 16:15:55
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renal
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Heritable and acquired disorders of tubular function
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  1. Purpose of tubulo-glomerular feedback (nephron)
    Constrict afferent arteriole to a malfunctioning nephron in order to prevent Na+, H2O loss in urine
  2. % of ultrafiltrate reclaimed by tubules
    Urine has variable concentration of these ions
    Urine has high concentration of these ions
    • 99%
    • Na+, Cl-
    • H+, K+, urea, NH3 [and organic anions, cations]
  3. How does the kidney function as an endocrine organ?
    • Synthesizes active Vit. D
    • Synthesizes erythropoietin
    • Metabolizes peptide hormones
  4. What two major biological molecules are synthesized by the kidney?
    Ammonia, glucose
  5. How does the kidney function as an immunological modulator?
    • Antigen presentation
    • Cytokine production
    • Antioxidant synthesis
    • Free radical scavengers
  6. What is the basic macroscopic unit of the kidney?
    Lobule
  7. What nephron structures are contained within the cortex of the kidney?
    Bowman’s capsule (glomerulus), PCT, DCT
  8. What nephron structures are contained within the medulla of the kidney?
    Looped tubules, peritubular capillaries, collecting duct
  9. What is the embryonic tissue precursor for the proximal nephron segments?
    Mesenchymal tissue
  10. What is the embryonic tissue precursor for the medullary collecting duct?
    Uroepithelium
  11. What are the five general ways the kidney can fail? Which way is most common?
    • Genetic defects
    • Toxicology/pharmacology
    • Immunological/infectious processes
    • Systemic diseases (most common)
    • Developmental processes
  12. What type of molecule holds tubule epithelial cells to the basement membrane?
    Integrins
  13. How can ions pass through epithelial junctions via the paracellular route?
    Integrins on the lateral membranes of two adjacent epithelial cells form a pore
  14. Are mitochondria concentrated at the apical or basolateral membrane of tubule epithelial cells? Why?
    Basolateral; the Na/K ATPases require energy
  15. What fraction of the GFR is reabsorbed by the PCT?
    ~60%
  16. What is the bulk reabsorbing segment of the nephron?
    PCT (isosmotic reabsorption)
  17. What is the salt recycling segment of the nephron? What is the purpose of salt recycling?
    Loop of Henle; maintain medullary osmotic gradient
  18. What are the diluting segments of the nephron?
    TALH, DCT
  19. What molecules are selectively reabsorbed and secreted in the cortical/medullary collecting duct?
    • Reabsorbed: NaCl, urea, [water]
    • Secreted: H+, K+
  20. T/F: The saltwater fish has a primitive nephron with a glomerulus.
    False – no glomerulus is required; the fish only needs to secrete biological waste molecules
  21. What “nephron” segments do freshwater fish have?
    • Glomerulus
    • Bulk reabsorber
    • Organic ion secretor
    • H+, K+ secretor / Na+ reabsorber
  22. What structure helps amphibians avoid desiccation while on land?
    Bladder
  23. What is the major difference between mammalian and amphibian nephron function?
    Magnitude of the medullary osmotic gradient (up to 1200 mOsm for mammals vs. 100 mOsm for amphibians)
  24. 5 general causes of renal tubular dysfunction
    • Non-lethal defects of tubule cell metabolism
    • Transporter loss of function
    • Transporter gain of function
    • Structural disorganization of epithelium
    • De-differentiation of epithelium
  25. What fraction of Na+ is reabsorbed by the PCT via the Na+/H+ exchanger?
    1/3
  26. What fraction of Na+ is reabsorbed by the PCT via the Na+/solute co-transporters?
    2/3
  27. Role of angiotensin II in PCT
    Upregulate Na+/H+ exchanger
  28. Role of catecholamines in PCT
    Upregulate Na/K ATPase
  29. Role of PTH in PCT
    Downregulate Na+/HPO4- cotransporter
  30. Describe the pathway for PCT HCO3- reclamation
    Intracellular carbonic anhydrase (CA) converts CO2 + H2O → H2CO3 → H+ + HCO3- → HCO3 transported across basolateral membrane, H+ transported across apical membrane → lumenal H+ combines with HCO3- → H2CO3 → extracellular CA converts H2CO3 → CO2 + H2O → CO2 enters cell
  31. What force(s) drive isosmotic reabsorption in the PCT?
    • High tonicity/hydrostatic pressure in the interstitial space (created by the basolateral Na/K ATPase)
    • High oncotic pressure in the capillaries caused by high [albumin] and low [H2O]
  32. How much albumin is filtered by the glomerulus daily?
    How much is actually excreted in the urine (i.e., not reclaimed by the PCT)?
    • 3 g
    • 25 mg
  33. What is the fate of albumin in the PCT?
    What is the fate of lipids (formerly bound to albumin) in the PCT?
    • Ubiquination --> proteosome
    • Segregation into surface granules --> recycling
  34. What is the favored substrate for ATP synthesis in the PCT?
    Glutamine
  35. What is the pathological basis of Fanconi’s Syndrome?
    Mitochondrial dysfunction → PCT atrophy
  36. Fanconi’s Syndrome
    What substances are found at abnormally high concentrations in the urine?
    Does it result in metabolic acidosis or alkalosis?
    • Glucose, amino acids, phosphate, Na+, K+, HCO3-
    • Acidosis
  37. How could increased protein presentation to the PCT cause Fanconi’s Syndrome?
    • Increased proteosomal activity → ATP depletion
    • Increased numbers of lysosomes
    • Increased heme byproducts → mitochondrial toxicity
  38. Describe the cAMP-dependent ADH pathway in the medullary collecting duct
    ADH binds V2 receptor → activate adenylate cyclase → increase cAMP → activate PKA → phosphorylate aquaporin-containing vesicles → vesicles fall off the microtubule tracts → can fuse with apical membrane
  39. Describe the IP3-dependent ADH pathway in the medullary collecting duct
    ADH binds V2 receptor → activate PLC → increase IP3 → release of intracellular Ca2+ stores → aquaporin-containing vesicles can fuse with apical membrane
  40. What are the symptoms of nephrogenic diabetes insipidus in…
    Adults
    Children
    • Headaches, changes in mental status after mild water deprivation
    • Polyuria, frequent bedwetting
  41. Nephrogenic diabetes insipidus
    What hormone signaling pathway is perturbed?
    What protein is involved?
    • ADH
    • Aquaporins (insertion is hampered)
  42. Besides a defect in aquaporin insertion into the MCD apical membrane, what other mechanisms could impede ability to make a concentrated urine?
    • Inability to transport NaCl or urea into the interstitum
    • Inability to maintain slow but adequate blood flow in MCD
    • Inability to secrete ADH
  43. Collecting duct principal cell
    Apical channel(s)
    Basolateral channel(s)
    Responsive to which hormone?
    • ENaC, ROMK1
    • Na/K ATPase
    • Aldosterone
  44. CD α intercalated cell
    Apical channel(s)
    Basolateral channel(s)
    H+ or HCO3- secreting?
    Upregulated in carnivores or herbivores?
    • H+ pump, Cl- channel, H/K ATPase
    • Cl-/HCO3- exchanger
    • H+
    • Carnivores
  45. CD β intercalated cell
    Apical channel(s)
    Basolateral channel(s)
    H+ or HCO3- secreting?
    Upregulated in carnivores or herbivores?
    • Cl-/HCO3- exchanger
    • H+ pump, Cl- channel, H/K ATPase
    • HCO3-
    • Herbivores
  46. % of filtered Na+ load reabsorbed in CD
    5%
  47. How does the transepithelial potential affect transport of Na+, K+, and H+ in the CD?
    The more Na+ is reabsorbed, the more K+ (principal cell) and H+ (α intercalated cell) is secreted
  48. In the CD, is the lumen positive or negative relative to the interstitum?
    Lumen negative
  49. What is the effect of aldosterone on the CD?
    Upregulate ENaC, ROMK1, Na/K ATPase
  50. What is the effect of ANP on the CD?
    Inhibit ENaC
  51. What is another name for Liddle’s Syndrome?
    Pseudohyperaldosteronism of the CD
  52. Are aldosterone levels elevated in patients with Liddle’s Syndrome?
    No
  53. Do patients with Liddle’s Syndrome respond to infused aldosterone?
    Yes – increased Na+ retention
  54. What ion imbalances and symptoms accompany Liddle’s Syndrome?
    • Hypertension
    • Hypokalemia
    • Metabolic alkalosis
  55. Do patients with Liddle’s respond to…
    Aldosterone antagonist
    ENaC blocker
    • No
    • Yes
  56. Molecular mechanism behind Liddle’s Syndrome
    Mutation in ENaC cytoplasmic PY domain → PY cannot bind Nedd → Nedd cannot target apical ENaC channels to ubiquination/proteosome pathway → decreased endocytosis of ENaC channels
  57. TALH
    % of Na+ load reabsorbed
    Apical ion transporters
    Diuretic family that blocks one of these transporters
    • 20%
    • Na/K/2Cl channel, K+ transporter
    • Loop diuretics (e.g., furosemide)
  58. Mechanism behind Bartter’s Syndrome
    Inhibition of Na/K/2Cl transporter, apical K+ transporter, or basolateral K+/Cl- cotransporter in the TALH
  59. DCT
    % of Na+ load reabsorbed
    Apical ion transporter
    Diuretic family that blocks this transporter
    • 10%
    • Na+/Cl- cotransporter
    • Thiazide diuretics
  60. Mechanism behind Gittleman’s Syndrome
    Inhibition of the apical Na+/Cl- cotransporter in the DCT
  61. What triggers the loss of differentiation/polarization of the tubular epithelium, following acute hypoxia?
    Decrease in ATP and increase in intracellular Ca2+
  62. Characterize these after hypoxic nephron damage:
    Brush border
    Tight junctions
    Attachment to ECM
    Reabsorptive function
    • Unstable
    • Loose
    • Loss of integrin attachment
    • Transformation to secretory phenotype
  63. Mechanism behind tubulo-glomerular feedback
    Nephron fails → increased lumenal Na+ reaches macula densa → cells swell → ATP release → production of adenosine → adenosine causes afferent arterioles to constrict → cut off renal blood supply to nephron
  64. How does the embryonic kidney retain patency of the tubule lumen?
    Fluid is secreted into the lumen (via apical CFTR Cl- channel)
  65. How does a normal tubule epithelial cell retain its absorptive phenotype?
    Ca2+ enters cell through apical polycystin channel → shut off cAMP and PKA → cannot phosphorylate CFTR containing vesicles → cannot maintain CFTR insertion in apical membrane
  66. What protein might be defective in polycystic kidney disease?
    Polycystin
  67. How does formation of a few kidney cysts cause widespread renal damage?
    • Bleeding
    • Stagnant urine → infection
    • Crowding of other tubules → obstruction, pressure damage

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