Signalopathies - Polycystic Kidney Disease

Question 1

What is Polycystic Kidney Disease (PKD)?

Answer 1

= most common potentially lethal genetic disorder

Cystic genetic disorder of the kidneys:

= autosomal dominant PKD (ADPKD) = most common = 12.5 M worldwide
= autosomal recessive PKD (ARPKD) = less common = ~1 in 20,000 live births

Multiple large fluid-filled cysts (typically in both kidneys)
= massive enlargement of kidneys
= disruption of kidney function and severe renal failure

Question 2

What are the genetics of PKD?

Answer 2

ADPKD - mutations in 2 genes
= PKD1 - polycystic kidney disease 1
= PKD2 - polycystic kidney disease 2

Mutations in both PKD1+2 needed for disease progression
= rapid proliferation of cells
= loss of structural relationship with neighbouring cells
= formation of large cysts

Question 3

What do genes PKD1 and PKD2 encode?

Answer 3

Encode the proteins:
= PC1 - polycystin-1
= PC2 - polycystin-2

PC1
= receptor like structure
= interacts with proteins at extra and intracellular sites

PCR2
= Ca2+ permeable channel
(homologous to TRP channels)
= EF hand domain

They interact via their C-terminal domains
= PC1-PC2 complex responds to ciliary bending
= may mediate the transduction of mechanical and chemical stimuli

Question 4

How does Ca2+ regulation of cAMP-dependent ERK activation link to cell proliferation and PKD?

Answer 4

= CROSSTALK

EXTRA READING

= ERK (extracellular signal-related kinase) pathway is downstream target of both Ca2+ and cAMP

= ERK involved in cell proliferation

= in response to a stimulus, Ca2+ activates the CaMKK and ACs
= production of cAMP
= cAMP then activates PKA
= which activates Ras/ERK pathway
= eventually leading to activation of ERK

Question 5

What happens in normal kidney cells?

Answer 5

= Ca2+ regulation of cAMP-dependent cell proliferation

B-Raf
= inhibited by ‘normal’ Ca2+ conc
= through PI3K and AKt

Raf-1
= inhbited by ‘normal’ cAMP conc
= through AC, cAMP and PKA

= inhibits cell proliferation

Question 6

What happens in polycystic kidney cells?

Answer 6

= Ca2+ regulation of cAMP-dependent cell proliferation

Low Ca2+ conc
= relieves inhibition of B-raf
= increases cAMP conc

High cAMP conc
= activation of B-Raf through Ras
(involves AC, cAMP conc, PKA)

Stimulation of cell proliferation through MEK / ERK

MAPK remodelling hypothesis:
= reduction of Ca2+ conc
= phenotypic remodelling
= increased expression of cAMP insensitive isoform (B-Raf)
= transmission of proliferation signals