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Fixing leaky kidneys

03 December 2019

Kidneys damaged by diabetes can start to leak out protein, and this can lead to kidney failure. But interesting new research shows that it might be possible to plug those leaks before they cause too much damage.  

For people with diabetes, the chances of also developing kidney disease are relatively high. In fact, people with diabetes are five times more likely to need either kidney dialysis or a kidney transplant. As diabetes progresses, the kidneys can become more damaged over time, until they no longer work properly. We call this diabetic kidney disease, or diabetic nephropathy, and it’s the main cause of kidney failureWhen your kidneys aren’t working properly, they leak things out into the urine that were supposed to be kept in the blood – things like protein.  

We can spot this kidney damage early on by looking for a specific protein, called albumin, in the urine. When there is albumin in the urine (which we call albuminuria), it can lead to additional complications like cardiovascular disease and other related issues. Sadly, there are very few treatment options for diabetic kidney disease. However, interesting research in mice suggests that there could be a way to stop albumin leaking into the urine, potentially offering a new treatment for those with diabetic kidney disease.  

glomerulus corpuscle open
Image thanks to Michiko Maruyama.

How do kidneys “leak”?

Your kidneys work like an incredibly smart filter: sifting blood for what should stay and what should go. One of the key parts of your kidneys that do this is a small structure called the glomerulus – you can think of the glomerulus like a sieve at the start of the filtering process. When your blood flows into the kidneys, and through the glomerulus to be filtered, it passes through a group of very flat cells called glomerular endothelial cells. One of the important jobs of these cells is to stop protein leaking out from the blood and they do this with the help of a specialised surface coating, made of sugars, which forms a barrier that we call the glycocalyx.   

Research just out from the Bristol University, by Dr Raina Ramnath working as part of Prof Satchell’s team in Bristol Renalhas uncovered that there are enzymes – specialised proteins in the body – that break down that glycocalyx barrier and let albumin pass out into the urineIn this case, it was a group of enzymes known as matrix metalloproteinases (MMPs) that were responsible for damaging the glycocalyxDr Ramnath highlights that there are higher levels of these MMPs in the diabetic mice than in ‘healthy’ micewhich helps to explain why the kidneys leak protein in diabetes 


Protecting the barrier

With MMPs (specifically two types known as MMP2 and MMP9) identified as the reason for the albumin leak across the glycocalyx, Dr Ramnath and the team set to work to figure out how to plug it. The solution was to use something we call an inhibitor. An inhibitor is a molecule that stops (inhibits) the action of another molecule. In this case, the inhibitor stopped MMP2 and MMP9 from damaging the glycocalyx barrier in the glomerulus 

The researchers gave the mice the MMP2 and MMP9 inhibitor for six weeks to see what would happen. It was a success! After six weeks on the inhibitor, the glycocalyx barrier was thicker and present across all of the flat glomerulus endothelial cellsThe MMP inhibitor plugged the albumin leak to stop it passing out into the urine.  

Treatment for diabetic kidney disease?

While this is fascinating research, we must remember that this is early-stage laboratory work. Dr Ramnath’s work has highlighted that inhibiting this group of MMPs in mice, can help to reduce albumin leaking out of the kidneys into the urineDr Ramnath told us that,  

Raina Ramnath
Dr Raina Ramnath

“Endothelial glycocalyx protection or restoration, through MMP inhibition, provides an attractive target for the treatment of diabetic kidney disease. This study would encourage pharmaceutical companies to develop more specific MMP inhibitors, that would reduce the adverse effects associated with broad-spectrum MMP inhibitors seen in some clinical trials. 

Findings from this work could lead to repurposing already existing drugs with MMP inhibitory properties for the treatment of diabetic kidney disease. This will be of benefit not only to diabetic kidney disease but also in ameliorating associated cardiovascular complications.  

There’s still a great deal of research to be done but it is incredibly exciting to see inhibiting MMPs singled out as a potential treatment for kidney disease in people with diabetes. 

Dr Ramnath’s results were published in the journal Kidney International and were funded by Kidney Research UK 


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