Innovations and Emerging Therapies to Combat Renal Cell Damage: NAD⁺ As a Drug Target

Acute kidney injury (AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is defined by an abrupt deterioration in renal function, clinically manifested by increased serum creatinine levels, decreased urine output, or both. To execute all its functions, namely excretion of waste products, fluid/electrolyte balance, and hormone synthesis, the kidney requires incredible amounts of energy in the form of adenosine triphosphate. Adequate mitochondrial functioning and nicotinamide adenine dinucleotide (NAD⁺) homeostasis are essential to meet these high energetic demands. NAD⁺ is a ubiquitous essential coenzyme to many cellular functions. NAD⁺ as an electron acceptor mediates metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis, serves as a cosubstrate of aging molecules (i.e., sirtuins), participates in DNA repair mechanisms, and mediates mitochondrial biogenesis. In many forms of AKI and chronic kidney disease, renal function deterioration has been associated with mitochondrial dysfunction and NAD⁺ depletion. Based on this, therapies aiming to restore mitochondrial function and increase NAD⁺ availability have gained special attention in the last two decades. Experimental and clinical studies have shown that by restoring mitochondrial homeostasis and increasing renal tubulo-epithelial cells, NAD⁺ availability, AKI incidence, and chronic long-term complications are significantly decreased. This review covers some general epidemiological and pathophysiological concepts; describes the role of mitochondrial homeostasis and NAD⁺ metabolism; and analyzes the underlying rationale and role of NAD⁺ aiming therapies as promising preventive and therapeutic strategies for AKI. Antioxid. Redox Signal. 35, 1449-1466.