From Proceedings of National Academy of Sciences, USA
Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease
Significance
Polycystic kidney diseases (PKDs) are genetic disorders in which multiple cysts grow in kidneys, leading to end-stage renal failure. Vasopressin antagonists (vaptans) currently used to treat PKDs have side effects due to liver toxicity. We report the characterization of Mambaquaretin-1, a Kunitz-fold polypeptide isolated from mamba venom that selectively and fully inhibits three major signaling pathways of the vasopressin type-2 receptor. Mambaquaretin-1 induces a purely aquaretic effect on mice and reduces cyst development in a mouse model. We produced mambaquaretin-1 by peptide synthesis and determined its X-ray structure, its binding mode, and functional properties. With high selectivity and without toxic metabolic byproducts associated with its peptidic nature, mambaquaretin-1 could become the preferential treatment for these disorders.
Abstract
Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein–coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 μ𝝁g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.
The venom of the green mamba — one the most dangerous snakes in Africa — might one day help to treat people who have a genetic disorder that affects the kidneys, according to a new study conducted in mice.
The disorder, called polycystic kidney disease, causes numerous cysts to grow in the kidneys. The disorder may lead to kidney damage, according to the National Kidney Foundation. But for babies born with a severe form of the disorder, the condition can also be deadly, according to the National Institute of Diabetes and Digestive and Kidney Diseases.
However, the new study was done in mice, and it is not clear yet if the venom compound may work to treat this disease in people who have the condition, said study author Nicolas Gilles, a venom researcher at the University of Paris-Saclay in France. Further studies are needed to look at this, he said.
Treatments that are currently available for polycystic kidney disease may help to alleviate some of its symptoms, such as high blood pressure, but there is currently no cure for the disease, the National Kidney Foundation says.
Green mamba bites may cause dizziness, nausea and irregular heartbeat, and can be fatal. In the new study, the researchers first extracted one compound from the venom, called mambaquaretin-1, according to the study, published today (June 19) in the journal Proceedings of the National Academy of Sciences.
The researchers then administered the venom compound to six mice with the kidney disease every day for 99 days. The study also included a group of control mice with the condition, which were instead given saline solution every day for 99 days. The mice that were given the compound seemed to tolerate it well, as the animals did not change their behavior during the experiment, the researchers said.
At the end of the experiment, the researchers measured the levels of markers for kidney function in all of the mice. Based on these measurements, the researchers concluded that the mice treated with the venom compound had better kidney function than the mice in the control group.
The number of cysts in the mice treated with the compound was reduced by one-third, the researchers found. The researchers also found that the ratio of cyst area to normal kidney tissue area decreased by 28 percent in the mice treated with the compound. Moreover, the total area of kidney cysts was reduced by 47 percent after the treatment, the scientists found. [Pick Your Poison: 7 Ways Venom Can Be Healing]
The compound seems to work by targeting the action of a receptor called the type-2 vasopressin receptor, which is involved in the disease, the researchers said.
So far, researchers have not looked at using venom from this snake to treat any other condition, Gilles told Live Science. However, based on this and other research, it is becoming more and more clear that, besides being rich in toxins, venoms are also a source of molecules that can target certain receptors in the body that are involved in human health, he said.
Making a Gift of Life
From The Conversation
At any one time, more than 1,400 Australians are on an organ transplant waiting list. The most common organs in demand are kidneys, followed by the liver and lung.
While the number of deceased organ donors in Australia has doubled since 2009, rates of live donor transplantation – where a person donates one kidney or, rarely, a portion of their liver – are relatively static.
In 2016, 265 Australians donated a kidney to a friend or relative, making up about a quarter of all kidney transplants. Live donor liver transplants are rare (only two occurred in Australia last year) and often donated from a parent to a child.
Who needs a kidney?
Kidneys filter toxins from the blood and regulate fluid balance. When kidneys are functioning so poorly a person needs dialysis to do the work for them, we say the person has “end stage kidney disease”.
In 2015, there were nearly 12,500 Australians undergoing dialysis. End stage kidney disease often occurs gradually and is commonly a result of diabetes, high blood pressure and types of autoimmune kidney disease called glomerulonephritis.
Many patients with end stage kidney disease would live longer and have a better quality of life following a kidney transplant compared to staying on dialysis. But the shortage of donor organs means preference is given to those likely to have better outcomes and reasonable life expectancy after transplantation.
Australian guidelines require patients have an 80% likelihood of survival at five years after transplantation to be eligible for the wait list. Tests are done to ensure the potential transplant recipient has acceptable heart health to undergo the operation, and that there are no cancers or infections that will be made worse by medications that suppress the immune system (“anti-rejection drugs”).
The donor’s kidney function is assessed, and the risk of them developing a kidney disease in future is evaluated. This is both to ensure the donor enjoys good kidney function after removal of their kidney, and that the recipient receives a well-functioning kidney. Donors also routinely undergo psychological evaluation.
Where do donors come from?
A potential recipient is encouraged to ask friends and family if they would be willing to donate a kidney. If not, the potential recipient can go on the deceased donor list to wait for a compatible kidney.
People often donate organs to their blood relatives, but it’s also possible to give a kidney to someone who is not related, such as a spouse or close friend. Some people use social media to solicit organ donations, and some have been successful. Specific matching sites also exist in countries such as the US, with the aim of getting healthy volunteers to altruistically donate a kidney.
But methods of acquiring a donor who is previously unknown to the recipient are controversial and generally discouraged in Australia for ethical reasons. In Australia, a person could donate a kidney altruistically to someone on the waiting list. In this situation, the donor and recipient do not find out each other’s identity.
The Australian paired-exchange program allows greater numbers of live donor transplants to occur through paired kidney donor swaps. For example, if Jane’s potential donor John is unsuitable to give her a kidney because of matching issues, and Bob’s potential donor Barbara is unsuitable to give him a kidney, Barbara can donate a kidney to Jane, and John can donate a kidney to Bob.
Last year, an altruistic donation kicked off a domino chain of six paired-exchange donations, with the final kidney from a paired exchange donor going to a patient on the deceased donor waiting list.
Live donors must be over 18, but it’s preferable if they are over 30 as older age at donation minimises their chance of developing an unexpected condition that threatens their kidney health down the track.
Do you need to be a ‘match’?
Different people have different combinations of proteins on the surface of their cells that allow the immune system to determine what is part of the body (self) and what are foreign agents (non-self). These proteins are determined by genes called human leukocyte antigens (HLA).
The immune system is designed to recognise self HLA so it doesn’t target its own tissues. It is advantageous to have high degrees of HLA match (also called tissue match) between a donor and recipient, but it’s not absolutely necessary. A closer degree of HLA match means the immune system is less likely to reject the kidney.
Usually people need to be the same blood group to donate a kidney. But some living donor transplants can occur across different blood groups. These are called ABO incompatible transplantation. For this to happen, the recipient must undergo plasmapheresis – a process in which antibodies (proteins that attack foreign invaders) are removed from their blood and they are given strong medication to suppress the immune system.
Only people with end stage kidney disease can be listed for deceased donor transplantation. But living donor transplants can be “pre-emptive”, taking place before the need for dialysis.
This has advantages, such as not having to take time away from work or study to do dialysis. People who undergo pre-emptive transplantion have a lower risk of death and loss of kidney transplant function compared to people who spend time on dialysis before getting a transplant.
Are there risks to donors?
Kidney donors usually remain in hospital for a few days after surgery, which is usually conducted as “keyhole surgery”. This involves a camera and instruments being inserted through a small incision and the kidney being pulled out through it.
Full recovery time is around six to eight weeks. Complications, such as bleeding or blood clots, related to the operation are rare. There is a very small risk of death around the time of the operation, estimated at 3.1 in 10,000 donors, or 0.031%. Although the patient populations differ, this is less than for other minor operations such appendicectomy (estimated in a recent study at 0.21%).
There is no long-term increased risk of death or heart disease. Donating a kidney is likely to cause a slight increase in blood pressure over time.
After donation, the remaining kidney increases its capacity to filter blood, and kidney function usually returns to 70-80% of the previous level. This is adequate, and does not result in any symptoms related to kidney disease.
Studies comparing kidney donors to equivalently healthy non-donors found kidney donation increases risk of end stage kidney disease about three- to five-fold. But the risk is very low to begin with (around 0.06% for a white US man and 0.04% for a white US woman).
The kidney donation experience is usually positive. In one study, 95% of kidney donors in the US rated their experience as good to excellent. They reported an improvement in their sense of meaning in life and self-esteem. But a degree of psychological stress related to donation was common, and 20% reported a financial burden.
The Australian government gives A$4.1 million to run the Supporting Living Organ Donors program. This scheme includes reimbursing employers for sick leave for those who donate an organ, as well as other initiatives that aim to remove financial barriers to organ donation.
More information about living kidney donation is available at Donate Life, Kidney Health Australia, and the Supporting Living Organ Donors program.
