L10.2 Regulation of kidney development II Flashcards Preview

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Flashcards in L10.2 Regulation of kidney development II Deck (14):
1

What does organ culturing allow?

  • 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

2

Compounds regulating kidney development

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

3

Limitations of genetically modified animals

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

4

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

  • 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

5

Features and function of BMP

  • 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

6

Wnt developing in kidney

  • 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

7

Effect of KO AT1/AT2?

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

8

Maternal insults regulating kidney development

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

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9

Kidney in programming 

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

10

Brenner hypothesis

  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

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11

Effect of BP in prenatal exposure to compounds in sheep models

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

12

Overview of low nephron number

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13

Effect of natural GC exposure in mouse models

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

14

Male and female differences

  • 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

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