Closing in on an optimal molecule for kidney injury

A designer molecule goes exactly where
it is needed for protection against kidney
injury during transplantation.

by Anne Crawford

Kidney ischemia-reperfusion injury (IRI) is common during transplantation, leading to compromised function in the kidney and increasing the chance of rejection of the new organ.

Now scientists in the Vascular Biology Group, Australian Centre for Blood Diseases, have refined a designer molecule that offers protection against IRI in research that may have translational significance to transplantation.

Reperfusion (reoxygenation) injury occurs after blood flow has been stopped causing ischemia (lack of oxygen), then restarted – in the case of kidney transplantation when blood vessels are tied off before the new kidney is transplanted. This activates the immune system which causes inflammation and vessel damage. It also occurs following a blood clot in a vessel after the clot is removed, for example after a stroke, after blood flow resumes.

Researchers led by Vascular Biology Group Head Professor Harshal Nandurkar and Professor Peter Cowan of St Vincent’s Hospital, had previously conducted studies that showed that the molecule CD39 protected against IRI in mouse models. CD39 is normally expressed on the cells lining blood vessels in the kidney but its expression is lost during IRI.

However, the molecule acts as an anti-clot agent as well as an anti-inflammatory one; if injected, it causes bleeding across the circulation system.

Dr Maithili Sashindranath, first author of a paper that appeared in the journal ‘Purinergic Signalling’, says the challenge was to get the molecule to specifically focus only on the affected area.

“We designed a ‘recombinant’ CD39 that is coupled with a fragment of a protein known as PSGL-1,” Dr Sashindranath said. “P-selectin glycoprotein ligand 1 (PSGL-1) attaches itself to P-selectin which is a molecule involved in forming blood clots, and is located on the vessel wall and binds to immune cells during inflammation.”

The molecule went exactly where it was needed, was shown to protect against IRI and could be used at a lower dose, she said.

“The paper acts as proof of principle that this targeting is a very good idea,” she said.

Dr Sashindranath said that Professor Karlheinz Peter, the group’s collaborator from Baker IDI, had successfully targeted CD39 to platelets to treat heart attack but that the Vascular Biology Group was the first to target it to the endothelium (vessel wall), as far as they are aware.

The researchers are in the process of targeting CD39 in other ways, and are examining its potential to treat both kidney IRI and in other organs where this occurs, such as in the brain, during a stroke.

“We hope it will be able to have an unprecedented role in minimising IRI in the kidney and the brain and that it can automatically be given safely to all patients treated for this without the side-effects of any sort of bleeding,” she said.
 
The research was supported by the NHMRC.

Reference

Sashindranath M, Dwyer KM, Dezfouli S3, Selan C, Crikis S, Lu B, Yuan Y, Hickey MJ, Peter K, Robson SC, Cowan PJ, Nandurkar HH. Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia-reperfusion injury. Purinergic Signal. 2017 Jun;13(2):259-265. doi: 10.1007/s11302-017-9558-3. Epub 2017 Mar 25.