Scientists identify role of key metabolism enzyme in kidney disease

Scientists have identified the role an enzyme, crucial to the body’s metabolism, plays in the development of kidney disease, opening the door to new methods of prevention and treatment of this increasingly prevalent, potentially fatal condition.

According to the World Health Organization (WHO), kidney disease has risen from being the 13th leading cause of death to the 10th. In 2019, 1.3 million people died from kidney disease, rising from 813,000 in 2000. But it’s often possible to slow or stop kidney disease from progressing to kidney failure if it’s detected and treated early.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme, a helper molecule, found in every single living cell. In addition to regulating various metabolic pathways, it is also involved in DNA repair and immune cell function. It’s crucial to maintaining metabolic homeostasis (equilibrium) through its effect on mitochondria, the cell’s power generators. Without sufficient levels of NAD+, our cells wouldn’t be able to generate the energy necessary to carry out their metabolic functions.

The kidney’s tubule cells require a lot of mitochondria-produced energy to perform their function, reabsorbing essential nutrients and excreting waste products and toxins. When the mitochondria in those cells are damaged, an inflammatory response is triggered that can result in kidney disease, leading to a build-up of fluid, electrolytes, and waste in the body.

Now, researchers at the University of Pennsylvania have used metabolomics – the study of small molecules found in blood and urine – to map metabolite changes in healthy and diseased mouse and human kidneys. Metabolites are very small molecules produced during metabolism; measuring them gives an insight into a person’s health status. This is the first time human samples have been used in metabolomic studies.

The researchers tested kidney samples from a healthy control group against samples from patients with diabetic kidney disease or kidney disease caused by high blood pressure (hypertension). They found that, in the diseased kidneys, NAD+ levels were significantly lower. To examine the disease mechanism underlying these differences, they conducted RNA-sequencing on the samples.

Finding a correlation between NAD+ levels and mitochondrial gene expression, the researchers concluded that lower NAD+ levels were a key feature of human kidney disease.

Moreover, when mice were given an over-the-counter supplement of NAD+ precursors, nicotinamide riboside or nicotinamide mononucleotide (NMN), to boost NAD+ levels, the tubule cell’s mitochondria were protected from damage, thereby preventing the progression to kidney disease.

“We hope that this research can lead to improved care in the future,” said Katalin Susztak, co-lead author of the study. “So when patients have metabolite changes, they can receive treatment before kidney disorders arise.”

The researchers hope their study will lead to further studies into the role of metabolites in kidney disease and the development of new methods of prevention and treatment.

“Identifying these downstream mechanisms that are sensitive to NAD+ is critical to understanding which conditions may benefit from NAD+ supplementation,” said Joseph Baur, co-lead author of the study.

The study was published in the journal Nature Metabolism.

Source: University of Pennsylvania

Scientists have identified the role an enzyme, crucial to the body’s metabolism, plays in the development of kidney disease, opening the door to new methods of prevention and treatment of this increasingly prevalent, potentially fatal condition.

According to the World Health Organization (WHO), kidney disease has risen from being the 13th leading cause of death to the 10th. In 2019, 1.3 million people died from kidney disease, rising from 813,000 in 2000. But it’s often possible to slow or stop kidney disease from progressing to kidney failure if it’s detected and treated early.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme, a helper molecule, found in every single living cell. In addition to regulating various metabolic pathways, it is also involved in DNA repair and immune cell function. It’s crucial to maintaining metabolic homeostasis (equilibrium) through its effect on mitochondria, the cell’s power generators. Without sufficient levels of NAD+, our cells wouldn’t be able to generate the energy necessary to carry out their metabolic functions.

The kidney’s tubule cells require a lot of mitochondria-produced energy to perform their function, reabsorbing essential nutrients and excreting waste products and toxins. When the mitochondria in those cells are damaged, an inflammatory response is triggered that can result in kidney disease, leading to a build-up of fluid, electrolytes, and waste in the body.

Now, researchers at the University of Pennsylvania have used metabolomics – the study of small molecules found in blood and urine – to map metabolite changes in healthy and diseased mouse and human kidneys. Metabolites are very small molecules produced during metabolism; measuring them gives an insight into a person’s health status. This is the first time human samples have been used in metabolomic studies.

The researchers tested kidney samples from a healthy control group against samples from patients with diabetic kidney disease or kidney disease caused by high blood pressure (hypertension). They found that, in the diseased kidneys, NAD+ levels were significantly lower. To examine the disease mechanism underlying these differences, they conducted RNA-sequencing on the samples.

Finding a correlation between NAD+ levels and mitochondrial gene expression, the researchers concluded that lower NAD+ levels were a key feature of human kidney disease.

Moreover, when mice were given an over-the-counter supplement of NAD+ precursors, nicotinamide riboside or nicotinamide mononucleotide (NMN), to boost NAD+ levels, the tubule cell’s mitochondria were protected from damage, thereby preventing the progression to kidney disease.

“We hope that this research can lead to improved care in the future,” said Katalin Susztak, co-lead author of the study. “So when patients have metabolite changes, they can receive treatment before kidney disorders arise.”

The researchers hope their study will lead to further studies into the role of metabolites in kidney disease and the development of new methods of prevention and treatment.

“Identifying these downstream mechanisms that are sensitive to NAD+ is critical to understanding which conditions may benefit from NAD+ supplementation,” said Joseph Baur, co-lead author of the study.

The study was published in the journal Nature Metabolism.

Source: University of Pennsylvania