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Purpose of tubulo-glomerular feedback (nephron)
Constrict afferent arteriole to a malfunctioning nephron in order to prevent Na+, H2O loss in urine
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% 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]
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How does the kidney function as an endocrine organ?
- Synthesizes active Vit. D
- Synthesizes erythropoietin
- Metabolizes peptide hormones
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What two major biological molecules are synthesized by the kidney?
Ammonia, glucose
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How does the kidney function as an immunological modulator?
- Antigen presentation
- Cytokine production
- Antioxidant synthesis
- Free radical scavengers
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What is the basic macroscopic unit of the kidney?
Lobule
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What nephron structures are contained within the cortex of the kidney?
Bowman’s capsule (glomerulus), PCT, DCT
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What nephron structures are contained within the medulla of the kidney?
Looped tubules, peritubular capillaries, collecting duct
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What is the embryonic tissue precursor for the proximal nephron segments?
Mesenchymal tissue
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What is the embryonic tissue precursor for the medullary collecting duct?
Uroepithelium
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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
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What type of molecule holds tubule epithelial cells to the basement membrane?
Integrins
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How can ions pass through epithelial junctions via the paracellular route?
Integrins on the lateral membranes of two adjacent epithelial cells form a pore
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Are mitochondria concentrated at the apical or basolateral membrane of tubule epithelial cells? Why?
Basolateral; the Na/K ATPases require energy
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What fraction of the GFR is reabsorbed by the PCT?
~60%
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What is the bulk reabsorbing segment of the nephron?
PCT (isosmotic reabsorption)
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What is the salt recycling segment of the nephron? What is the purpose of salt recycling?
Loop of Henle; maintain medullary osmotic gradient
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What are the diluting segments of the nephron?
TALH, DCT
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What molecules are selectively reabsorbed and secreted in the cortical/medullary collecting duct?
- Reabsorbed: NaCl, urea, [water]
- Secreted: H+, K+
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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
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What “nephron” segments do freshwater fish have?
- Glomerulus
- Bulk reabsorber
- Organic ion secretor
- H+, K+ secretor / Na+ reabsorber
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What structure helps amphibians avoid desiccation while on land?
Bladder
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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)
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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
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What fraction of Na+ is reabsorbed by the PCT via the Na+/H+ exchanger?
1/3
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What fraction of Na+ is reabsorbed by the PCT via the Na+/solute co-transporters?
2/3
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Role of angiotensin II in PCT
Upregulate Na+/H+ exchanger
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Role of catecholamines in PCT
Upregulate Na/K ATPase
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Role of PTH in PCT
Downregulate Na+/HPO4- cotransporter
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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
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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]
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How much albumin is filtered by the glomerulus daily?
How much is actually excreted in the urine (i.e., not reclaimed by the PCT)?
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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
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What is the favored substrate for ATP synthesis in the PCT?
Glutamine
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What is the pathological basis of Fanconi’s Syndrome?
Mitochondrial dysfunction → PCT atrophy
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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
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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
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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
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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
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What are the symptoms of nephrogenic diabetes insipidus in…
Adults
Children
- Headaches, changes in mental status after mild water deprivation
- Polyuria, frequent bedwetting
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Nephrogenic diabetes insipidus
What hormone signaling pathway is perturbed?
What protein is involved?
- ADH
- Aquaporins (insertion is hampered)
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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
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Collecting duct principal cell
Apical channel(s)
Basolateral channel(s)
Responsive to which hormone?
- ENaC, ROMK1
- Na/K ATPase
- Aldosterone
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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
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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
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% of filtered Na+ load reabsorbed in CD
5%
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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
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In the CD, is the lumen positive or negative relative to the interstitum?
Lumen negative
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What is the effect of aldosterone on the CD?
Upregulate ENaC, ROMK1, Na/K ATPase
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What is the effect of ANP on the CD?
Inhibit ENaC
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What is another name for Liddle’s Syndrome?
Pseudohyperaldosteronism of the CD
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Are aldosterone levels elevated in patients with Liddle’s Syndrome?
No
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Do patients with Liddle’s Syndrome respond to infused aldosterone?
Yes – increased Na+ retention
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What ion imbalances and symptoms accompany Liddle’s Syndrome?
- Hypertension
- Hypokalemia
- Metabolic alkalosis
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Do patients with Liddle’s respond to…
Aldosterone antagonist
ENaC blocker
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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
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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)
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Mechanism behind Bartter’s Syndrome
Inhibition of Na/K/2Cl transporter, apical K+ transporter, or basolateral K+/Cl- cotransporter in the TALH
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DCT
% of Na+ load reabsorbed
Apical ion transporter
Diuretic family that blocks this transporter
- 10%
- Na+/Cl- cotransporter
- Thiazide diuretics
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Mechanism behind Gittleman’s Syndrome
Inhibition of the apical Na+/Cl- cotransporter in the DCT
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What triggers the loss of differentiation/polarization of the tubular epithelium, following acute hypoxia?
Decrease in ATP and increase in intracellular Ca2+
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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
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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
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How does the embryonic kidney retain patency of the tubule lumen?
Fluid is secreted into the lumen (via apical CFTR Cl- channel)
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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
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What protein might be defective in polycystic kidney disease?
Polycystin
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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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