L10.2 Regulation of kidney development II

Question 1

What does organ culturing allow?

Answer 1

• Allows identification of function of various peptides
  
  • Glomeruli visualised by immunohistochemistry (WT-1 → stain podocytes or PNA)
  • Ureteric tree visualised by staining with calbindin-28 or cytokeratin

Question 2

Compounds regulating kidney development

Answer 2

• BMP-4
• GC
  
  • Dysregulate >1500 gene expression in fetal kidney
• Alcohol

Question 3

Limitations of genetically modified animals

Answer 3

• KO → could cause another gene to compensate
• Difficult to eliminate possibility of off target effects

Question 4

Features and funtion of GDNF (Glial cells derived neurotrophic factor)

Answer 4

• Glial cell line-derived neurotrophic factor
• Important in signalling of uretic bud growth by interacting with cRET in the uretic bud
• Binds to GFRα
• KO → bilateral renal agenesis
• Partial KO → ~↓30% nephrons
  
  • May have no phenotype difference

Question 5

Features and function of BMP

Answer 5

• Bone morphogenetic proteins
• Acts on activin like kinase (ALK) cell surface R
• Inhibits branching morphogenesis by inhibiting GDNF
• Expressed in wolffian duct in pregnancy
• -ve regulation by BMP4 → controls branching
• KO BMP 7 → Renal dysplasia

Question 6

Wnt developing in kidney

Answer 6

• Wnt11 expressed at tip
  
  • KO → ↓30% neprhons
• Wnt 4 at pretubular aggregate and also on renal vesicle on nephron
  
  • KO → Small kidneys, lack pretubular aggregates

Question 7

Effect of KO AT1/AT2?

Answer 7

• KO AT1 → Vascular thickening, abnormal medulla
• KO AT2 → CAKUT

Question 8

Maternal insults regulating kidney development

Answer 8

• Exposed to low protein diet → ↓AT1b, ↑AT2
  
  • Shows that exogenous factors activate renal responses and impair development
  • Important in regulation of sexual dimorphism

Question 9

Kidney in programming

Answer 9

1. Nephron number → ↑BP and further ↓nephron number
2. Altered Na homeostasis
3. Impaired regulation of RAS

Question 10

Brenner hypothesis

Answer 10

1. Low nephron
2. ↓filtration SA
3. ↓filtered load
4. ↑Na and fluid renteion → ↑ECF
5. ↑arterial pressure
6. ↑glomerular capillary pressure
7. ↑single nephron GFR → glomerular hypertrophy
8. Glomerulosclerosis (death) → ↓nephrons more

Question 11

Effect of BP in prenatal exposure to compounds in sheep models

Answer 11

• Pregnant sheep given synthetic GC for 2 days
• BP of offspring → Worsened with time
  
  • Everything else were similar, only nephron numbers were different

Question 12

Overview of low nephron number

Answer 12

Question 13

Effect of natural GC exposure in mouse models

Answer 13

• AT1 and AT2 affected early in embryonic development
• Results in ↓nephron numbers in males and females at 30days of life
  
  • Nephron formation is impaired

Question 14

Male and female differences

Answer 14

• Kidneys dysregulated to manage the GC exposure and persists throughout life
• Sex specific insults/adaptations
  
  • Outcomes mostly regulated by the placenta
  • Males develop high BP and renal dysfunction