Edocriniology of the Kidney (Erythropoietin)

What is Erythropoietin? EPO

glycoprotein hormone

Produced by the kidney cells

Hyposxia stimulates the production of EPO

EPO stimulates production of red blood cells

What is the structure of the EPO?

4 alpha helix structure, stabalised by 2 disulfide bonds

Glycosylation important for:

• biological activity

• stability increased half life

What type of receptor is EPO receptor?

Expressed in eyrthoid progenitors

Enzyme coupled receptor

What is the action of the activated EPO receptor?

How does EPO signalling promotes erythroid differentiation?

EPO acts on CFU-E progenitors and proerythroblasts to maintain their survival and facilitate terminal maturation

EPO acts on the EPO dependent stages to force them to suvive proliferate etc.

What happens if EPO signalling is disrupted?

Anaemia

How is EPO expression regulated? in normoxia and hypoxia?

Hypoxia inducible factor (HIF)

transcription factor that promotes the expression of EPO and other genes

In normoxia:(normal levels of oxygen

• HIF is rapidly degraded  

• O2 sensitive prolyl hydroxylase enzymes hydroxylate the HIFalpha subunit—→ Ubiquitination by the PVHL ubiquitin ligase complex→ proteasomal degradation 

In hypoxia:

• PHD enzymes are inactive

• HIF1alpha and HIF1beta dimers translocate to the nucleus and drive the expression of EPO and other genes

Pharmacological targets: PHD INHIBITORS FOR TE TREATMENT OF ANEMIA

What Is oxygen shunting?

Oxygen shunting: the are terriers and veins run side by side int he kidney, the kidney needs relatively low oxygen compared to the blood flow it recieves.

Shunting means oxygen moving directly to veins without passing though capillary supply tissues basically a shortcut the oxygen gradient is large enough for this to happen.

How do the kidneys act as an oxygen sensor?

Because of oxygen shunting, the amount of oxygen reaching the O2 sensing cells is low and influence

D strongly with blood flow

It creates low oxygen environment so basically also ways hypoxic conditions in the renal cortex/outer medulla

This makes it very sensitive to changes

→ Small drop in renal blood flow

→ Less oxygen reaches the sensing fibroblasts

→ Hypoxia-inducible factor (HIF) accumulates

→ EPO production increases

Without oxygen shunting, oxygen levels would stay too high to detect subtle changes.

How does oxygen shunting and the function of oxygen sensing cells in the kidney cause the secretion etc of EPO?

If blood flow is decreased, the oxygen shunting causes even less oxygen to reach the sensing cells.

Lower blood flow means less oxygen delivery means kidney senses hypoxia (not enough RBC)

The shunting removes a bigger fraction of already reduced oxygen supply

Very sensitive change in oxygen supply.

Low oxygen → inactivates PHD, allows HIF alpha to accumulate and then HIF switches EPO gene causes the secretion of EPO.

RENAL EPO producing cells REWATCH SLIDES AND TRY TO MAKE SMTH ABOUT IT :(