L9.3 Programming and Reprogramming

Question 1

What are adults born small susceptible to in the kidneys?

Answer 1

• ↓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

Question 2

Timeframe of nephrogenesis

Answer 2

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

Question 3

Critical periods for nephron endowment

Answer 3

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

Question 4

Limitation of using a sheep as a model

Answer 4

• Sheep has different placenta

Question 5

Why are GCs given to mothers?

Answer 5

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

Question 6

What features are apparent for growth restricted offsprings at 6 months

Answer 6

• 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

Question 7

Difference b/w male and female growth restricted offsprings

Answer 7

Question 8

Molecular link b/w IUGR and nephron development

Answer 8

• GC, GH, IGF…
• Leptin

Question 9

What processes are Leptin critical for?

Answer 9

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

Question 10

What is the role of leptin?

Answer 10

• 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

Question 11

Relationship b/w leptin and obesity

Answer 11

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

Question 12

Postnatal leptin levels

Answer 12

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

Question 13

Result of Leptin antagonism

Answer 13

• 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

Question 14

Overview of leptin in nephrogenesis

Answer 14

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

Question 15

Changes in signalling targets from cross-fostering

Answer 15

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