The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease

Abstract

Early-stage detection of chronic kidney diseases (CKD) is important to treatment that may slow and occasionally halt CKD progression. CKD of diverse etiologies share similar histologic patterns of glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Macro-vascular disease and micro-vascular disease promote tissue ischemia, contributing to injury. Tissue ischemia promotes hypoxia, and this in turn activates the hypoxia-inducible transcription factors (HIFs). HIF-1α and HIF-2α, share a dimer partner, HIF-1β, with the aryl hydrocarbon receptor (AHR) and are each activated in CKD and associated with kidney cellular nicotinamide adenine dinucleotide (NAD) depletion. The Preiss-Handler, salvage, and de novo pathways regulate NAD biosynthesis and gap-junctions regulate NAD cellular retention. In the Preiss-Handler pathway, niacin forms NAD. Niacin also exhibits crosstalk with HIF and AHR cell signals in the regulation of insulin sensitivity, which is a complication in CKD. Dysregulated enzyme activity in the NAD de novo pathway increases the levels of circulating tryptophan metabolites that activate AHR, resulting in poly-ADP ribose polymerase activation, thrombosis, endothelial dysfunction, and immunosuppression. Therapeutically, metabolites from the NAD salvage pathway increase NAD production and subsequent sirtuin deacetylase activity, resulting in reduced activation of retinoic acid-inducible gene I, p53, NF-κB and SMAD2 but increased activation of FOXO1, PGC-1α, and DNA methyltransferase-1. These post-translational responses may also be initiated through non-coding RNAs (ncRNAs), which are additionally altered in CKD. Nanoparticles traverse biological systems and can penetrate almost all tissues as disease biomarkers and drug delivery carriers. Targeted delivery of non-coding RNAs or NAD metabolites with nanoparticles may enable the development of more effective diagnostics and therapies to treat CKD.

Transient inhibition of sodium-glucose cotransporter 2 after ischemia/reperfusion injury ameliorates chronic kidney disease

“…Of particular importance is the maintenance of the NAD + pool through 3 major pathways in kidney cells. It may have implications for our findings: (a) the sodium-monocarboxylate transport (Preiss-Handler pathway), (b) the salvage pathway, and (c) de novo biosynthesis ( 49 – 51 ). It is noteworthy that the preservation of ETC integrity induced by Dapa in our study is likely associated with the restoration of the NAD + /NADH ratio, since these proteins favor the oxidized form of this coenzyme ( 47 ).…”

The role of nicotinamide adenine dinucleotide salvage enzymes in cardioprotection

“…Based on the author’s knowledge, there is no available literature to date with direct evidence of NAPRT’s influence on cardiac health. But the research on other applications including cancer [ 51 ], sepsis/septic shock [ 52 ], and treatment in prostate, ovarian, colorectal, and pancreatic disease [ 53 – 55 ] showed great potential. However, NAPRT appears as a driver in inflammatory processes to control the activation of macrophages necessary to recover from acute inflammatory diseases such as sepsis and septic shock [ 56 ].…”

“…The combined role of NAMPT and NAPRT in inflammation was also observed [ 49 ]. Another study on colorectal cancer (CRC) showed that the duration of disease-free survival time and overall survival time from CRC is indicated by NAMPT or NAPRT expression and the excessive level of NAMPT/NAPRT indicates the improper prognosis of patients with CRC in a distinct mechanism [ 52 ]. There are several research groups already working to find out the combined effect of NAMPT and NAPRT in different clinical domains, but to date, no conclusive data are available related to the combined effect on cardiovascular application.…”

The AKI-to-CKD Transition: The Role of Uremic Toxins

“…During AKI, β-oxidation decreases and ATP synthesis is compensated through aerobic glycolysis (insufficient to meet NADH and FADH 2 cofactor requirements), followed by anaerobic glycolysis (leading to lactate synthesis). Activation of the HIF-1α factor and activation of AhR [175] and mitochondrial dysfunction [176] are both causes and consequences of the transition from normoxic to anaerobic metabolism. In addition, the processes involved in the progression of renal pathology (collagen deposition, chronic inflammation, etc.)…”