L9.3 Programming and Reprogramming Flashcards Preview

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Flashcards in L9.3 Programming and Reprogramming Deck (15)
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What are adults born small susceptible to in the kidneys?

  • ↓nephron endowment → increase risk of hypertension
    • Nephron number established at birth
      • ↓nephron number → associated with high BP
  • Higher plasma renin
    • Changes in Na channels
    • ↑GFR → damage glomerulus
  • Altered ANGII R expression
    • → Altered renal function
    •  → Hypertension


Timeframe of nephrogenesis

  • Gestation around 40 weeks
  • Nephrogenesis begins soon after conception (finishes around 37 weeks)
    • Babies born small → ↓nephron number


Critical periods for nephron endowment

  • Nephrogenesis
    • Nephrogenesis continues postnatally in rats → allows postnatal intervention
  • Cross-fostering define critical periods of nephron development and programing of ↑BP


Limitation of using a sheep as a model 

  •  Sheep has different placenta


Why are GCs given to mothers?

  • Given to mother for babies who may be born early
    • Aids Lung development
    • May have adverse effects in offspring


What features are apparent for growth restricted offsprings at 6 months

  • Low nephron number
  • Glomerular hypertrophy (↑renal BF)
  • Normal glomerular volume
  • ↑BP by 9 weeks
  • ↑renal AT1 R.
  • ONLY in males, not females
    • Females only have decrease nephron number but does not dev hypertension


Difference b/w male and female growth restricted offsprings


Molecular link b/w IUGR and nephron development

  • GC, GH, IGF…
  • Leptin


What processes are Leptin critical for?

  • Critical for nephrogenesis and organogenesis
    • Kidney, pancreas, thymus, ovary


What is the role of leptin?

  • Primary role → regulate appetite → ↓food intake and ↑activity
    • Via hypothalamus
    • Leptin binds to R on cell membrane
      • Other proteins phosphorylated → altered JAK/STAT signalling and ↑gene transcription
  • Involved in proliferation and cell differentiation


Relationship b/w leptin and obesity

  • Low/high leptin = obesity
  • Loss of functional leptin R in brain → energy imbalance and obesity


Postnatal leptin levels

  • Leptin surge post-natally
    • 5-10 folds
  • Reduced to adult levels at day 35


Result of Leptin antagonism

  • Reduces organogenesis (similar phenotype to growth restricted offspring)
  • Reduce leptin conc in offspring suckled by mother which has reduced protein diet
  • IUGR → ↓leptin made by fat stores in pup → ↓production/transfer by placenta and mammary


Overview of leptin in nephrogenesis

  • Essentially IUGR → ↓Leptin conc → ↓nephrogenesis → High BP
  • Cross-fostering (nutritional leptin supplements) → restores leptin conc → restore nephron endowment → normal BP



Changes in signalling targets from cross-fostering

  • Although plasma leptin restored → Altered leptin signalling targets not restored
  • But Nephrogenesis still restored