Gene Models And Nephron Function Flashcards by Eira jane

Main function of nephron

Tubular reabsorption
- Movement of ions, water and small molecules into capillaries
Each kidney has ~1-1.5 million nephron (therefore 1-1.5 million glomeruli)

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Glomerular filtration of plasma

~20% plasma removed
180L/day filtrate
Plasma vol =2.75L
Max urine vol. excretion=23L
Plasma filtered 65 times/day

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What is permitted/ restricted in filtration by glomerular?

Permitted:
- H2O
- Small molecules
Restricted:
- Blood cells
- Proteins

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Ultrafiltrate - the plasma processed by renal tubule - has passed through semipermeable membrane with v. small pores (ie through glomerular)

Conc of ions in plasma same as in Bowman’s capsule
Consists of protein free plasma
1% protein filtered (albumin) (small proteins)
Large proteins in urine=glomerula breakdown
Small proteins in urine=from proximal tubule

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What are the pathways of tubular transport?

Transcellular pathways = across the cell
- Reabsorption: ions, water, solutes
- Secretion ( from blood into lumen of tubule)
Paracellular secretion/ absorption
- between cells - tight junctions mediate

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Reabsorption in the proximal tubule

Bulk reabsorbing epithelium
High apical SA
Lots of mitochondria (ATP) - energy needed
Bulk reabsorption: 70% filtrate reabsorbed (70% of Na, 70% of 180L water reabsorbed)
~100% of glucose and amino acids reabsorbed
90% bicarbonate (HCO₃^-) reabsorbed (regulation of pH and body fluids)

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Movement across proximal tubule (basolateral cell membrane proteins)

Na/K ATPase - ubiquitous transport protein (found everywhere)
- hydrolyses ATP to drive influx of 3Na out and 2K in - against electrochemical grdt
- primary active transport protein
- maintaining low intracellular Na conc
K channel
- sets -ve membrane potential
- driving force of Na influx (mediated by proteins)

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Movement across membranes of proximal tubule cells (apical membrane)

Na/ Glucose transport molecule: SGLT1&2
- Facilitated diffusion (Na coupled transport)
- Net reabsorption of glucose
- Secondary active transport
Phosphate reabsorption: NaPi11
Na/AA
- Net reabsorption of both (100% AA reabs)

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Movement across membranes of proximal tubule cells (Paracellular Movement)

Water follows (Na) isosmotically
Conc ~ same between start and end of proximal tubule

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Proximal tubule: NaPi11 KO mice phenotype

Young animals struggle to maintain phosphate
Early abnormal skeletal development
Older mice show compensation
Not too much difference in skeleton in older mice

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Proximal tubule: SGLT1&2

14 transmembrane spanning domains
extra and intercellular projections
binding sites for Na and glucose - flips over and releases them into cell
Slightly different sequence between 1 and 2
1 monmer - fully functional protein

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What are the symptoms and cause of Familial Renal Glycosuria?

Inherited mutation in SGLT2
Increased urinary glucose (can’t reabsorb as much glucose) : few to a 100g/day
Normal plasma glucose
No obvious kidney damage
No general tubule damge
Carriers - heterozygous - mild symptoms
Autosomal recessive - severe symptoms

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Bicarbonate handling (reabsorption) in the proximal tubule (apical membrane)

Maintaining body fluid pH

NHE3: Na/H⁺exchange protein
- Na in H out (H+HCO₃^-=H₂CO₃)
Carbonic anhydrase (H2CO3) on outer surface of apical membrane
- CO2 freely diffusible
- H2O - water channels (aqua porin 1)
- Combine to form H2CO3 in cell

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Bicarbonate handling (reabsorption) in the proximal tubule (basolateral membrane)

Na/HCO₃^- transport protein
- high conc of HCO3
- drives reabsorption of Na and HCO3
High water permeability

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Proximal tubule: NHE3 KO mice

KO incapable of making NHE3
Lose ability to reabs HCO3 - plasma HCO3 levels drop
HCO3 is an important buffer (esp in plasma)
Increased H ( because of HCO3 decrease) = decreased pH - particaluarly effects excitable cells)
Decreased systolic BP as less fluid reabsorption - increased urine flow rate
(decreased EC fluid vol=decreased BP

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Proximal tubule: effects of NHE3 KO

Inhibit H secretion
Inhibits Na and HCO3 transport
Decreased fluid reabsorption
Decreased plasma HCO3
Decreased pH
Decreased ECFV
Decreased BP

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Secretion by the proximal tubule

Removal of plasma protein bound substances
Removal of foreign compounds
- eg penicillin (plasma levels weren’t reaching therapeutic levels - lots of it was secreted into urine)

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Function of the Loop of Henle (LoH)

Fluid is essentially the same throughout loop
Concentration of urine
Reabsorption of Na, Cl, H2O, Ca, Mg
Site of action of loop diuretics

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LoH: Loop structure

Thin and thick ascending limbs are water impermeable.

Movement across membranes of Thick Ascending Limb (TAL)

Apical membrane

NKCC2: Na/Cl/K co-transport protein
- must bind 1:2:1 to move into cell
ROMK (Kir1.1): K channel

Basolateral membrane

CLCK and Barttin (beta/accessory subunit) work together for normal function
- Net reabs of Cl

Paracellular reabsorption

Na and Cl reabsorption drives reabs of Ca and Mg

TAL: Causes of Bartter’s Sydrome

Recessive inheritance
Loss of function mutations in:
- NKCC2 or
- ROMK (isn’t enough K in plasma so NKCC2 and therefore CLCK can’t work) or
- CLCK/ Barrtin (Cl can’t leave so increased Cl conc so NKCC2 can’t bring in Cl - grdt works against it)

TAL: Barrter’s sydrome symptoms

Salt wasting (loss of Na and Cl in urine)
Polyuria (increase in urine flow rate) (reduced H2O reabs b/c loss of Na and Cl in urine)
Hypotension
Hypokalaemia (low plama K)
Metabolic alkalosis (high pH)
Hypercalciuria (Ca in urine) - increased risk of:
- Nephrocalcinosis - stone formation

LoH: Loop Diuretics

Furosemide (Frusemide) and Bumetanide block NKCC2
Treatment of high BP
- Particularly in pts where high BP is due to high ECFV eg oedema
Side effects:
- Bartter’s-like symptoms

Function of Early Distal Tubule (DT)

Reabsorption of Mg, Na, Cl
dilute fluid
Sensitive to thiazide diuretics

Movement across membranes Early DT

![]() Apical membrane * NCC: Na/Cl transport * (driven by Na/K ATPase & K channel) * Mg channel * eflux pathway not currently known * Mg reabs Basolateral membrane * Na/K ATPase * CLCK & Barttin: Cl reabs Paracellular reabs * Water ( driven by net reabs of Na and Cl)

Early DT: Cause of Gitelman's Syndrome

* Loss of function mutation in NCC * Recessive inheritance ![]()

Early DT: Gitelman's Syndrome symptoms

* Early DT rather than TAL =\> not Bartter's but similar symptoms * Salt wasting * Polyuria * Hypotension * Hypokalaemia * Metabolic alkalosis * _Hypocalciuria_ - low Ca in urine =\> unclear why but suggests loss of Na and Cl reabs (Bartters - high Ca) ![]()

Early DT: Thiazide Diuretics

* Chlorothiazide - blocks NCC * Treatment for high BP * Side effects: Gitelman's-like symptoms ![]()

What does being heterozygous for a mutation in ROMK, NCC, or NKCC2 protect against?

* Hypertension * Mean BP lower than normal * Less likely to have problems associated with hypertension

Function of the Late Distal, Connecting Tubules and Cortical Collecting Duct (CCD)

* Conc. of the urine * Reabs of Na and H2O * Secretion of K and H

Cell Types Of The Late DT and CCD

1. Principal * Main site for Na and H2O reabs * K and H secretion 2. Intercalated * alpha-IC (a-IC) and beta-IC (B-IC) * Depending on acid-base status of body - causes change * a-IC \<=\> B-IC * H secretion and reabs * HCO3 reabs and secretion

Movement across Principal Cell (apical) membrane

![]() * Low intracellular Na conc * ENaC: epithelial Na channel * down electrochemical grdt * regulated * ROMK: K _secreted_ * determines urine K content depending on plasma K * Aquaporin 2 * up/down regulated to change urine flow rate

Movement across Principal Cell (basolateral) membrane

![]() * Kir 2.3 * recycling K * Aquaporin 3&4

Diseases associated with the principal cell

* Diabetes insipidus (AQP2) * Liddle's syndrome (ENaC) * Pseudohypoaldosteronism ![]()

Principal cell diuretic

* Amiloride * Blocks ENaC * Treatment: high BP * K sparing diuretic ![]()

Movement across a-IC membrane

* H secretion and HCO3 reabs (HCO3 created by cell - not filtered HCO3) ![]() Apical * Proton pump pumps H into urine Basolateral * AE1: HCO3/Cl pump * Cl channel - recycling Cl Typically in excess acid - more a-IC than B-IC

DT Acidosis cause

* Genetic inheritance * Mutation in AE1 * Mutant protein is mistargeted * Trafficking defect - protein trafficks to apical membrane * HCO3 is not reabs - it's secreted * Struggle to retain sufficient HCO3 ![]()

DT Acidosis symptoms

* Nephrocalcinosis (srone formation) * Metabolic acidosis (low pH)

Movement across B-IC membrane

* H and Cl reabsorbs and HCO3 secretion ![]() Apical * AE1: HCO3/ Cl pump Basolateral * Proton pump - reabs H * Cl channel pH too high - alkylosis

Medullary CD

* Low Na permeability * High H2O and urea permeability in presence of vasopressin * Kidney- use urea to allow us to produce conc urine

Kidney: Na reabs summary

* PT 70% * LoH 20% * DT & CCD 9% (ENaC -aldosterone regulates ENaC) * Total = 99% * Most of filtered Na reabs

Kidney: H2O reabs summary

* PT 70% * LoH 5% * DT & CCD 24% (regulated by vasopressin) * Total = 99% * Most of filtered water reabs

Kidney: K reabs summary

* PT 80% * LoH 20% * DT & CCD (K secreted in urine)

Kidney: H reabs & secretion summary

* Secretion: * PT * Principal cell * a-IC * Reabs: * B-IC

Kidney: HCO3 reabs & secretion summary

* Secretion * B-IC * Reabs * PT * Principal cell * a-IC

Acute Renal Failure

* Causes: pre-renal/renal/ post renal (urinary blockage) * Fall in glomerular filtration rate over hrs/days * Impaired fluid & electrolyte homeostasis * Lasts ~1week (reversible) * Accumulation of nitrogenous waste * Treatment: dialysis

Acute Renal Failure symptoms

* Hypervolaemia (expansion of ECFV) * Oliguria (reduced urine vol) due to low GFR * causes hypertension * Hyperkalaemia - lack of K secretion * cardiac excitabilty - increased risk of arrhythmia * Acidosis - depression of CNS * High urea/ creatine * impaired mental function * nausea * vomiting