Cystic Kidney Disease

Question 1

What are the functions of the kidney?

Answer 1

Fluid homeostasis
Salt/Water Balance (Blood pressure)
Urine formation (waste excretion)

Question 2

What are the cystic kidney disease?

Answer 2

Autosomal Dominant (Adult) PKD
Autosomal Recessive (Childhood0 pkd
Nephronophthisis
Bardet-Biedel Syndrome
Meckel Gruber syndrome
Oro-facial digital syndrome

Question 3

What are the features of autosomal dominant Polycystic Kidney disease?

Answer 3

1:400-1:1000 population
Leading cause of End Stage Renal Disease
Accounts for 8% of people on dialysis
There is no known cure with dialysis or a transplant being the only treatments available

Question 4

What are the genetics of autosomal dominant polycystic kidney disease?

Answer 4

There are two genes which may be responsible, PKD1 (85% of cases) and PKD2 (15% of cases)
These encode the polycystin 1 and 2 proteins
The observed PKD1 mutations are typically varied with deletions, frameshifts, insertions and splicing however the type of mutation has no bearing on the clinical presentation of the disease
The observed PKD2 mutations are truncations which result in inactive protein

Question 5

What are the cellular characteristics of Polycystic kidney disease?

Answer 5

Increased epithelial cell proliferation
Epithelial de-differentiation
Loss of apical/basal polarity
Fluid secretion into the cyst (incorrect sorting of ion channels/transporters)

Question 6

What are the three different types of cilia?

Answer 6

Motile cilia (9+2) which perform a characteristic wave beat
Nodal (9+0) + dynein these are embryonic organizers which perform a circular beat
Primary (9+0) these are non motile or sensory cilia

Question 7

What is the anatomy of a primary cilium?

Answer 7

There is a cilia membrane which surrounds an axoneme which is a bundle of fibers which extend from a basal body which attaches to the cell membrane

Question 8

What are the characteristics of primary cilia?

Answer 8

They develop from a basal body which is one of the centrioles
They are resorbed during cell division and reformed afterwards

Question 9

What is intraflagellar transport?

Answer 9

This is a process of building and maintaining cilia

IFT particles-protein complexes and ciliary precursors/ signalling molecules

Question 10

What is the function of primary cilia?

Answer 10

They are signalling machine with primary cilia are tiny rigid structures that extend from almost every cell in the body, they serve as a type of antenna sensing chemical signals and relaying them into the cell

Question 11

What is the difference between motile and primary cilia?

Answer 11

Motile cilia have a pair of central tubules that allows the structure to move side to side often in a co-ordinated wave like motion
Primary cilia however not have these central tubules and as a consequence they do not move
Motor proteins drag particles up and down the cilium and may carry signals processed at the ciliums tip into the cell

Question 12

How does Autosomal Dominant Polycystic Kidney Disease progress?

Answer 12

In a subset of the kidney cells there will be a loss of a normal copy of the allele which leads to the initiation of disease progression
There will be growth and expansion of this subset of cells which may progress to fibrosis, apoptosis and collapse of cysts

Question 13

What are the five pieces of evidence which points to polycystic kidney disease being due to the role of primary cilia in cystogenesis?

Answer 13

Loss of primary cilia through use of mouse models results in polycystic kidney disease
Cystoproteins localize to the cilia
Cystoprotein knockout mice have PKD
Loss of mechanotransduction signalling in cystoprotein knockout mice (their cilia no longer bend in response to flow)
No Ca2+ Response to flow in polycystin
Planar Cell polarity pathway is disrupted in cilia mutants

Question 14

What are the mouse models that show that loss of primary cilia causes PKD?

Answer 14

Tg737 Oak ridge Polycystic Kidney Mouse
This gene encodes Polaris and in these mice it leads to short cilia and cystic kidneys
KIF3a knockout mice also have cysts

Question 15

How do primary cilia normally react to flow?

Answer 15

They bend this changes the conformation of the PCI-PC2 complex which is Ca2+ channel which then allows calcium influx
This calcium then diffuses down the cilia to the cell where it combines with Ryanodine leading to Ca2+ release and subcellular activity

Question 16

What is the flow induced Ca signalling that cilia are responsible for?

Answer 16

Flow stimulation leads to polycystin mediated mechanosensation
Then through some poorly understood mechanism (potentially G-proteins, Calcium mobilization or cAMPs) there is a change in cell-cell communication, protein expression, activity and localization and cell cycle regulation
The cell-cell communication controls whether the cells will grow to generate a cyst or a tubule

Question 17

How is planar cell polarity pathway disrupted in cilia mutants?

Answer 17

PCP signalling and cilia pathways maintain polarity
Tubular flow in the early nephron could act on the PCP pathway
Defective sensing/PCP signalling could lead to cyst formation