- The normal functioning of kidneys requires high levels of energy and kidney disease is characterized by a disruption of that energy metabolism.
- Nicotinamide adenine dinucleotide (NAD) is a molecule that plays a key role in energy metabolism and cellular signaling, with studies suggesting changes in NAD metabolism with kidney disease.
- A new study using kidney samples from humans and mice suggests that NAD deficiency plays a central role in mediating inflammation and metabolic changes observed in kidney disease.
- The study also reports that supplementation with precursors used by the body for NAD synthesis helped to protect mice against kidney disease.
- These findings could help in the development of therapeutics for kidney disease.
Kidney disease is associated with inflammation and impaired functioning of mitochondria, which are the organelles involved in energy production.
A recent study published in the journal Nature Metabolism reports that kidney disease is associated with lower levels of nicotinamide adenine dinucleotide (NAD), a molecule that plays a vital role in energy metabolism.
Moreover, the researchers say they found that the supplemental use of precursors or building blocks for NAD synthesis could restore NAD levels and help to prevent kidney injury in mice.
These protective effects of NAD precursors on kidney health were mediated by ameliorating mitochondrial dysfunction, subsequently reducing inflammation and kidney damage.
“[Our study reveals] that patients with kidney disease, as well as mouse models of kidney disease, exhibit low levels of nicotinamide adenine dinucleotide (NAD) in their kidneys,” said Dr. Katalin Susztak, a study author and a professor of medicine at the University of Pennsylvania.
“The findings suggest a potential connection between NAD deficiency and the development of kidney disease,” she told Medical News Today. “Furthermore, the study found that supplementing mice with nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) protected them from the progression of kidney disease. NR and NMN are precursors to NAD and have been shown to boost NAD levels in previous research.”
“The promising results from the mouse models have sparked interest in conducting further studies to investigate the potential benefits of NR and NMN supplementation for patients with kidney disease. By analyzing the effects of these supplements on human subjects, researchers hope to gain a better understanding of their therapeutic potential and whether they can effectively mitigate the development and progression of kidney disease,” added Susztak.
Kidney disease and energy metabolism
The kidneys are responsible for maintaining electrolyte and fluid balance and the filtration of blood to remove waste and toxins.
These processes are conducted by nephrons, which are the structural and functional units in the kidney.
Each of the about 1 million nephrons present in the kidney is composed of a cup-like structure called the glomerulus and a complex tubular system. The blood is initially filtered in the glomerulus and the ultrafiltrate consisting of water and small molecules then passes into the renal tubules.
The renal tubules are involved in the reabsorption of nutrients and other useful small molecules back into the bloodstream while eliminating waste and toxins via urine. These processes are energy intensive and exposure to toxins or oxygen deprivation can lead to the disruption of energy metabolism in the renal tubules.
The mitochondria are cell organelles responsible for converting nutrients into chemical energy needed for all cellular processes. Consistently with their high energy demand, kidneys have a high number of mitochondria.
Previous studies have shown that kidney disease is associated with the disruption of mitochondrial function.
Nicotinamide adenine dinucleotide (NAD) is a key molecule that plays a central role in energy metabolism in the mitochondria. NAD also aids the function of several enzymes in the cell. Studies have shown that NAD metabolism is impaired in kidney injury.
NAD can be produced anew via the de novo synthesis pathway using the amino acid tryptophan. In addition, NAD can also be recycled via a salvage pathway from nicotinamide (NAM) and nicotinamide riboside (NR). NAM and NR are converted to nicotinamide mononucleotide (NMN), which is subsequently converted to NAD.
Studies in rodents have shown that supplementation with NAM, NMN, and NR can protect against the deleterious effects of kidney injury. Similarly, there is data to suggest similar protective effects of NMN and NR in humans with kidney disease.
However, the mechanisms underlying the actions of these NAD precursors in individuals with kidney disease are not well understood. In the present study, the researchers further examined how changes in NAD metabolism contribute to kidney disease.
Impact on NAD metabolism
The study consisted of kidney samples from 25 subjects with kidney disease caused due to diabetes or hypertension.
The researchers compared differences in the expression of metabolites, which are the intermediate or by-products of metabolism, and genes in the samples from the individuals with kidney disease with those obtained from 25 individuals without kidney disease.
The researchers reported that the NAD pathway was down-regulated in individuals with kidney disease, showing lower levels of NAD, NR, and NAM. However, individuals with kidney disease did not show lower levels of NMN. In addition to these changes in the NAD salvage pathway, the researchers say they also found changes in the de novo synthesis pathway.
Gene expression studies revealed that NAD expression levels were positively correlated with the levels of expression of genes involved in metabolic pathways in the mitochondria. In addition, lower NAD gene expression levels were associated with higher levels of a gene involved in cell death, also known as apoptosis.
The researchers then examined whether similar changes were observed in mice with or without kidney injury. The researchers injected the mice with the chemotherapy drug cisplatin to induce kidney injury.
Mice with kidney injury also showed lower NAD levels and changes in metabolites involved in the NAD synthesis pathways that were similar to those observed in humans. Examination of gene expression pathways in mice revealed reduced expression of enzymes involved in the NAD de novo synthesis pathway. In contrast, similar changes were absent in the salvage pathway.
Protective effects of NAD precursors
The researchers say these results suggest that the kidney injury did not impact the function of the NAD salvage pathway.
Thus, they suggest that supplementation with NAD precursors used by the salvage pathway could potentially ameliorate the effects of kidney injury.
Indeed, the treatment with NMN or NR, starting immediately before the cisplatin injection, helped to reduce the effects of kidney injury in mice. Specifically, supplementation with NMN or NR resulted in fewer pathological signs of tubule damage and lower expression of markers of tissue injury and cell death in kidney tubules. In addition, these NAD precursors helped normalize NAD levels in the kidney.
The treatment of mice with cisplatin led to mitochondrial dysfunction and supplementation with NAD precursors protected against mitochondrial impairment and helped attenuate changes in metabolic pathways.
Kidney injury induced by cisplatin led to the increased expression of genes associated with inflammation and the infiltration of the kidney tissue with immune cells. NAD precursor supplementation helped decrease these inflammatory responses in the mice with cisplatin-induced kidney injury.
Among the inflammation-associated genes that showed elevated expression included genes for proteins such as RIG-I that can detect viral RNA in the cell during viral infection and help elicit an immune response. A previous study demonstrated that leakage of RNA from mitochondria can also stimulate the expression of the DDX58 gene that encodes the RIG-I protein.
Consistent with this, the researchers said, they found that kidney injury induced by cisplatin led to the leakage of RNA from mitochondria, subsequently stimulating DDX58 expression. Moreover, the reduction of NAD levels in cultured mice kidney cells by the inhibition of an enzyme involved in NAD synthesis led to an increase in the expression of DDX58. In contrast, NAD precursors restored NAD levels and prevented the leakage of RNA from the mitochondria into the cytoplasm, thus, inhibiting RIG-I activation.
The researchers found that the levels of NAD in human kidneys were associated with the expression levels of DDX58, the gene that encodes RIG-I, and other genes involved in cytosolic RNA sensing. In addition, DDX58 gene expression levels were associated with a decline in kidney function and signs of kidney injury.
The researchers said these results suggest that kidney disease in humans may also lead to a decline in NAD levels, subsequently causing the activation of a similar pathway involving the activation of the cytosolic RNA sensing pathway and inflammation.
Implications of the kidney disease study
These findings could potentially inform the development of therapeutics for kidney disease, according to Dr. Diane Triolo, a nephrologist with Holy Name Medical Center in Teaneck, New Jersey.
“This study has the potential to change how we approach the treatment of kidney disease,” she told Medical News Today. “As of now, our treatments have focused on treating diseases that affect the kidney – for example, improving diabetic and blood pressure control – but nephrologists have been limited in the resources for treating the kidney itself.”
“This study has demonstrated a potential new pathway in treatment by identifying NAD depletion as well as the cytosolic release of mitochondrial RNA and RIG-I activation as a cause of kidney injury. By identifying these pathways, the future treatment of kidney disease has dramatically improved by targeting these areas and bringing hope and potential cures to the millions of people affected,” added Triolo.
“This groundbreaking research opens up new avenues for exploring the role of NAD in kidney disease and potentially paves the way for novel treatments,” noted Suztak. “While further investigation is required, these findings offer hope for future advancements in the management and prevention of kidney disease.”
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