Discovery may pave the way for treating chronic kidney disease

Therapy Breakthroughs 5. sep 2023 3 min Associate Professor, Kathrin Weyer Written by Morten Busch

Chronic kidney disease (CKD) is now the leading cause of death among noncommunicable diseases, and treatment has long been ineffective, but there is some light at the end of the tunnel. Researchers have found that a specific protein already known for its role in cardiovascular disease, proprotein convertase subtilisin/kexin type 9 (PCSK9), has a previously unknown and crucial function in the kidneys. Since an antibody treatment against PCSK9 has already been approved, the new discovery is a beacon of hope for new and improved treatment of people with CKD.

CKD poses a growing challenge globally and is currently the most common cause of death of all the noncommunicable diseases. More than 10% of the world’s population (more than 800 million people) are affected by kidney disease, and lifestyle changes or medications targeting high blood pressure and high cholesterol are not very effective treatments. Researchers have now discovered that a protein known to be a key regulator of cholesterol metabolism has a crucial role in the kidneys. This has potential for new treatment options.

“We discovered that PCSK9, which affects cholesterol levels in the blood and increases the risk of cardiovascular disease, has completely new and unexpected effects in the kidneys. We found that PCSK9 regulates a receptor in the kidneys that controls the amount of protein excreted in the urine. This knowledge can potentially be used to treat people whose kidneys are overloaded and therefore have accumulated protein in their urine,” explains Kathrin Weyer, Associate Professor, Department of Biomedicine, Aarhus University.

Remarkable how little is known

The kidneys are the cleansing organs of the body. They filter the blood to remove waste products and toxins and release substances such as sugar and amino acids back into the bloodstream. When the kidneys fail, redundant or harmful substances accumulate in the body, which can lead to poisoning, oedema and, in the long term, increased risk of heart attacks and strokes, the leading causes of death in Denmark, where more than 10% of adults have CKD.

“In the kidneys, megalin is the receptor that drives protein reabsorption and thus the amount of protein excreted in the urine. If megalin no longer functions optimally, the system becomes overloaded, leading to proteinuria, an abnormally high level of protein in a person’s urine,” says Kathrin Weyer.

Proteinuria is an important indicator of kidney disease and a critical risk factor for developing CKD. The researchers closely examined megalin and thereby how efficient the kidneys are reabsorbing filtered proteins.

“Given how important the kidney is and how serious the situation is when it malfunctions, it is remarkable how little we know about exactly how it works. A few years ago, I became intrigued to understand how the kidneys handle proteins and we stumbled on PCSK9 when examining possible links between cardiovascular diseases and the kidneys,” adds Kathrin Weyer.

PCSK9 appears to be directly involved

PCSK9 is a key regulator of lipid metabolism in the liver, but several studies suggested that PCSK9 potentially also affects kidney diseases and the high level of protein excreted in the urine. The researchers therefore set out to investigate how PCSK9 affects the protein reabsorption process by the kidneys and how this may contribute to the development of proteinuria.

“We showed in mice and then humans that PCSK9 interacts with megalin, which captures proteins that escape through the kidney’s glomerular filtration barrier. Mice without megalin had elevated urinary PCSK9 excretion, whereas mice with elevated levels of PCSK9 showed a decrease in megalin in the kidneys. So they appeared to be linked,” explains Kathrin Weyer.

Even more interesting was that disease conditions enhanced the effect. When the kidney glomerular filtration barrier was destroyed, the amount of PCSK9 ending up in the kidneys increased greatly, resulting in both enhanced tubular PCSK9 uptake and urinary PCSK9 excretion.

“When we examined the mechanism more closely, we found that targeted inhibition of PCSK9 increased kidney megalin and reduced urinary albumin excretion. PCSK9 thus appears to be directly involved in regulating urinary protein excretion by binding to megalin. This leads to downregulation of megalin and reduced uptake of proteins in the kidneys,” says Kathrin Weyer.

Previously unknown link

These findings highlight a previously unknown association between kidney function, cholesterol metabolism and cardiovascular health. Interestingly, the study also shows that manipulating PCSK9 levels affects not only kidney function but also the liver. This suggests that this complex communication between the kidneys and the liver may be exploited to develop new treatment strategies.

“The kidneys and liver, two of the body’s most vital organs, have long been known for their independent roles in how the body functions. So our new study sheds new light on a previously unknown link between them that can help to revolutionise the treatment of people with kidney and liver diseases,” explains Kathrin Weyer.

However, PCSK9 is not a new therapeutic target. Today, people with cardiovascular disease worldwide are treated with PCSK9 inhibitors, a specific antibody used to lower elevated cholesterol levels. It was also therefore important for the researchers to determine whether PCSK9 inhibition can also be used to treat people with kidney diseases.

“We found that the antibody that inhibits PCSK9 helped to protect megalin from downregulation by PCSK9 – at least in mice with a specific kidney disease called nephrotic syndrome. This led to less protein being excreted in the urine, which suggests that investigating the use of PCSK9 inhibitors to reduce proteinuria among people with CKD may be a good idea,” concludes Kathrin Weyer.

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