Diabetic Kidney Disease

Diabetes is a medical condition characterized by high blood sugar levels that occurs when the body either doesn’t produce enough insulin or doesn’t have a proper response to insulin. Diabetes affects an estimated 9.4 percent of all Canadians and can result in potentially life-threatening complications.

One of these complications that often develops is diabetic kidney disease (DKD), which is the leading cause of kidney failure in North America.

“DKD places a significant burden on our healthcare system,” says Dr. Joan Krepinsky, a clinician-scientist at the Hamilton Centre for Kidney Research, which is part of The Research Institute of St. Joe’s Hamilton. “However, the current standard of care for DKD can only slow disease progression, with many patients developing end-stage kidney disease and requiring costly therapies including dialysis or kidney transplant. There is a major need to identify new therapeutic targets to prevent DKD progression.”

Thankfully, Dr. Krepinsky and her team have uncovered a novel biological mechanism of DKD that has led them to a promising therapeutic target.

Kidney Research Pillar

Dr. Krepinsky is currently working with Novo Nordisk and the Empire Discovery Institute in a collaborative program called LeapRx to develop another type of treatment for DKD that may help prevent DKD from progressing. This treatment – known as peptide therapy –uses a string of amino acids known as a peptide. Peptide therapy is very common in treating different conditions; for example, insulin and semaglutide (Ozempic®) treatments are just two types of peptide therapies that are commonly administered to manage diabetes.

We tend to think about the pancreas when we hear diabetes, but other organs are involved in the condition as well. High blood sugar is the hallmark symptom of diabetes, and it can affect the cells inside the kidneys, potentially resulting in DKD.

High blood sugar specifically affects two proteins in the kidney: glucose-regulated protein 78 (GRP78) and alpha-2-macroglobulin (α2M). In people with normal blood sugar levels, GRP78 works inside the kidney cells to help make sure the kidneys are functioning properly. When there is too much glucose in the bloodstream, such as in the case of diabetes, GRP78 can move from the inside of the cell to the cell surface. In this new location, it is known as cell surface GRP78, or csGRP78.

People with diabetes also have higher kidney levels of α2M, which is usually a type of blood protein that can change its shape when it encounters certain enzymes. When this shape changes, a part of the α2M molecule that was previously hidden becomes visible. This new configuration is known as activated α2M, or α2M*.

α2M* typically isn’t present in the kidneys, except in the case of high blood sugar. The newly revealed part of α2M* fits very snugly with csGRP78. With csGRP78 residing on the surface of the kidney cells, these two proteins can come into frequent contact in the kidneys and bond together. Unfortunately, the bonding of these proteins causes a chain reaction that produces fibrotic tissue (scarring) in the kidneys. As scar tissue builds up, kidney function becomes worse over time and can eventually lead to kidney failure.

Dr. Krepinsky and her team are developing a peptide that can bond with α2M* before GRP78 gets the chance to, meaning that csGRP78 and α2M* won’t be able to create any fibrotic tissue in the kidneys.

“Stopping the interaction between these proteins may represent a new therapeutic target to prevent fibrosis development in DKD,” said Dr. Jackie Trink, a former grad student of Dr. Krepinsky who worked closely on this project at St. Joe’s. “The next step is to develop the peptide so that we can conduct human trials to determine how effective this treatment is.”

Dr. Krepinsky is working with other researchers to take the next steps in developing this novel treatment. Dr. Anthony Rullo at McMaster University, who is an expert in how to make proteins and peptides, is currently helping to identify a version of it that is suitable for human trials. Dr. Matthew Lanktree, a clinician-scientist at the Hamilton Centre for Kidney Research, is conducting genetic analyses to investigate whether any genetic variants of csGRP78 or α2M are associated with DKD. Finally, Yaseelan Palarasah, an investigator at the University of Southern Denmark, is providing critical reagents to be able to detect levels of the active form of α2M in blood and urine. This will allow the team to more accurately determine how effective this peptide treatment is once they begin studying it in humans. It may also help to identify which people may benefit from treatment with the peptide.

This research project has the potential to prevent DKD from becoming worse and progressing to kidney failure, reducing the need for advanced therapies like dialysis and kidney transplant. With this novel peptide treatment, the healthcare system can see a reduced economic burden and, more importantly, many people living with diabetes may be able to enjoy a higher quality of life.

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