NAD+ Enhancers as Therapeutic Agents in the Cardiorenal Axis
The interplay between the heart and kidneys, known as the cardiorenal axis, plays a crucial role in coordinating cardiac and renal function. Cardiorenal syndromes (CRS) refer to the complex interplay between heart failure and renal dysfunction, which can lead to significant morbidity and mortality. Recent evidence has highlighted the central role of altered nicotinamide adenine dinucleotide (NAD+) metabolism in the onset and progression of cardiorenal diseases.
NAD+ is a pivotal coenzyme in cellular metabolism, participating in diverse signaling pathways such as energy production, DNA damage repair, gene expression, and stress response. Compelling research suggests that strategies designed to boost cellular NAD+ levels hold promise as a therapeutic approach for both cardiovascular and renal disorders.
In this comprehensive review, we explore the implications of NAD+ metabolism in the cardiorenal axis, focusing on the potential of various NAD+ boosting strategies, including the use of NAD+ precursors, poly(ADP-ribose) polymerase (PARP) inhibitors, sirtuin activators, and other emerging approaches such as CD38 blockade and nicotinamide phosphoribosyltransferase (NAMPT) activation.
Cardiorenal Axis: A Complex Interplay
The heart and kidneys are physiologically intertwined, and their dysfunction often manifests in a phenomenon known as cardiorenal syndromes (CRS). CRS are clinically classified into five subtypes based on the duration of the disease (acute or chronic) and the organ that initiated the disorder (heart or kidneys).
In CRS type I, also known as acute cardiorenal syndrome, an acute worsening of heart function leads to acute kidney injury (AKI). This often occurs in the setting of acute cardiac diseases, such as acute decompensated heart failure (ADHF) or ischemic events. CRS type II, or chronic cardiorenal syndrome, is characterized by chronic abnormalities in heart function that progressively worsen renal function, as seen in chronic heart failure (CHF) patients.
Conversely, CRS type III, or acute renocardiac syndrome, occurs when AKI contributes to the development of acute cardiac injury. CRS type IV, or chronic renocardiac syndrome, describes a scenario where chronic kidney disease (CKD) leads to chronic heart injury, disease, and/or dysfunction. Finally, CRS type V, or secondary cardiorenal syndrome, arises when cardiac and renal injury are simultaneously present due to an underlying systemic disease.
Biomarkers play a crucial role in the diagnosis, risk prediction, and prognosis of cardiorenal syndromes. These include cardiac-specific markers like B-type natriuretic peptide (BNP) and kidney-specific markers such as neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C.
NAD+ Metabolism and the Cardiorenal Axis
NAD+ homeostasis is achieved through a delicate balance between its biosynthesis and consumption. NAD+ can be generated via three main pathways: the de novo pathway (from tryptophan), the Preiss-Handler pathway (from nicotinic acid), and the salvage pathway (from nicotinamide, nicotinamide mononucleotide, and nicotinamide riboside).
NAD+ serves as a cofactor in various enzymatic reactions, but it is also consumed by sirtuins, PARPs, and cADP-ribose synthases, which use NAD+ as a substrate to catalyze important cellular processes such as deacetylation, ADP-ribosylation, and calcium signaling, respectively.
Deregulation of NAD+ metabolism has been implicated in the pathogenesis of both cardiovascular and renal diseases. In the cardiovascular system, NAD+ depletion has been observed in various conditions, including myocardial ischemia-reperfusion injury, cardiomyopathy, heart failure, and atherosclerosis. Similarly, in the kidney, NAD+ deficiency has been linked to the development of AKI and CKD, often due to impaired NAD+ synthesis or excessive consumption.
Therapeutic Potential of NAD+ Enhancers
The intimate relationship between NAD+ depletion and cardiorenal diseases has sparked interest in strategies aimed at boosting cellular NAD+ levels as a potential therapeutic approach. These include:
NAD+ Precursor Supplementation: Compounds such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) have demonstrated beneficial effects in various preclinical models of cardiovascular and renal diseases.
PARP Inhibition: Inhibiting the NAD+-consuming enzymes of the PARP family has been shown to preserve NAD+ levels and confer cardioprotective and renoprotective effects in animal studies.
Sirtuin Activation: Activation of the NAD+-dependent sirtuin family of deacetylases has emerged as a promising strategy to mitigate cardiovascular and renal complications, given their involvement in regulating inflammation, oxidative stress, and mitochondrial function.
Alternative Approaches: Emerging strategies such as CD38 blockade and NAMPT activation have also demonstrated the potential to enhance NAD+ levels and provide therapeutic benefits in the cardiorenal context.
While the preclinical evidence supporting the use of NAD+ enhancers in cardiorenal diseases is compelling, the translation of these findings to the clinic has been limited. Ongoing and future clinical trials will be crucial in evaluating the safety, tolerability, and efficacy of these interventions in human patients.
Challenges and Future Directions
One of the key challenges in the field is the limited NAD+ enhancing potential of the classical NAD+ precursors, which typically only achieve a two-fold increase in intracellular NAD+ levels. The discovery of next-generation NAD+ enhancers, such as the reduced forms of NMN (NMNH) and NR (NRH), which can increase NAD+ to a much greater extent, may help overcome this limitation.
Moreover, the majority of the clinical trials conducted so far have been of relatively short duration, lasting only a few weeks. Evaluating the long-term effects of NAD+ enhancement on cardiorenal outcomes will be crucial to fully understand the therapeutic potential of these strategies.
Lastly, the synergistic effects of combining different NAD+ boosting approaches, such as NAD+ precursor supplementation and sirtuin activation, remain largely unexplored. Exploring these combined interventions may unlock additional therapeutic avenues for addressing the complex interplay between the heart and kidneys.
In conclusion, the modulation of NAD+ metabolism holds significant promise as a therapeutic strategy for cardiorenal diseases. As the field continues to evolve, the integration of preclinical insights, emerging NAD+ enhancers, and well-designed clinical trials will be essential to translate these promising findings into effective therapies for patients suffering from the devastating consequences of cardiorenal syndromes.