Kidney disease and diabetes: Searching for answers at the molecular level

From a certain vantage, the quest to defeat diabetes encompasses more than just one disease. Diabetes can affect many systems in the body over time, with complications potentially arising in organs such as the eyes, skin, feet, heart and kidneys.
Indeed, there are many diabetes patients among the roughly 100 million people worldwide with chronic kidney disease. So as Ping Wang, M.D., seeks ways to address diabetic kidney injury, his work could lead to therapies for all who face kidney disease. New developments are much needed, because right now solutions are lacking.
Ping H. Wang, M.D.
Ping Wang, M.D.
“Diabetes is one of the leading causes of kidney failure,” said Wang, professor and chair of the Department of Diabetes, Endocrinology & Metabolism at City of Hope. “We don’t really have specific treatments for chronic kidney disease, and if it advances to end-stage renal failure, patients either need dialysis or a kidney transplant. People are suffering, and we need to find viable options for them.”
The path to providing those options leads the physician-researcher back to the laboratory. The answers that make the biggest difference are likely to start at small scales, with the cellular processes that regulate the kidney in health and go awry in disease.

Where the power lies

In his investigations into diabetes and its complications, Wang is concerned with one part of the cell in particular: the microstructure that serves as its power plant, the mitochondrion.
Under normal circumstances, mitochondria are prompted to take up sugar byproducts by a cascade of molecular messaging that starts when the hormone insulin binds to a cell. Once activated, the mitochondria use those sugar byproducts to process oxygen from the blood. The product is a molecule called ATP, the cell’s chemical energy source.
However, with their fundamental role in metabolism, mitochondria can cause major problems when they aren’t working properly. Wang makes an analogy to the engine of an automobile.
“An old car runs on a lot of gasoline and doesn’t generate a lot of horsepower, but produces a lot of pollution,” he said. “The same thing happens with mitochondria when they aren’t working well: They don’t produce enough energy, and they produce toxic byproducts that can lead to kidney failure.”
In 2009, he and his research group revealed a link in the chain of biochemical signals by which insulin sets mitochondrial action into motion. They pinpointed a pathway labeled AKT as playing an important role. A recent finding from Wang’s lab is showing how the same pathway might also be relevant for treating chronic kidney disease.

Evidence for a new therapeutic target

Late last year, the journal Kidney International published a study led by Wang presenting early evidence that activating the AKT pathway could confer protection to kidney cells.
The researchers developed two laboratory models, one for defective AKT signaling and the other for robust AKT activity in mitochondria. Challenged with kidney injury, AKT-poor models fared poorly, with only about 23% surviving, while the AKT-rich experienced far better outcomes, with about 77% surviving.
“We found that a mechanism of diabetes participated in the development of kidney injury,” Wang said. “It might turn into an opportunity for us to develop new strategies to improve the outcome of kidney disease, including among diabetes patients.”
He and his research team are following up on the vital first step of identifying a potential therapeutic target, with investigations aiming to single out an existing drug that promotes AKT signaling, or design a new one altogether.

On a mission

Wang emphasizes that this line of research is part of a much larger effort underway both in the Department of Diabetes, Endocrinology & Metabolism and the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope.
“Our mission is to help improve the lives of people facing diabetes,” he said. “We want to develop new strategies to better prevent and treat the disease and its complications.”
City of Hope has a long history of advances in understanding and addressing diabetes. These include the technology behind synthetic human insulin, developed by the research institute’s lead donor and namesake, Arthur Riggs, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery.
Today’s Riggs Institute is home to innovative scientists tackling every element of diabetes. Investigators unraveling the causes of — and potential treatments for — its complications include renowned biochemist Rama Natarajan, Ph.D., chair of the Department of Diabetes Complications & Metabolism and the National Business Products Industry Professor in Diabetes Research. Among many breakthroughs, she demonstrated how inherited factors not encoded in DNA underly diabetic kidney disease.
“City of Hope has been a longtime leader in studying the molecular mechanisms and the basic science of diabetic kidney disease,” Wang said. “I am excited at the prospect of adding to that legacy.”