{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRenalase (RNLS) is a secreted flavin adenine dinucleotide–dependent amine oxidase that was originally discovered as a kidney‐derived enzyme capable of metabolizing circulating catecholamines – including dopamine, epinephrine, and norepinephrine – thereby modulating cardiac contractility and systemic blood pressure. Reduced plasma renalase levels have been observed in patients with end‐stage renal disease, suggesting that a deficiency in its activity may contribute to the increased cardiovascular morbidity seen in kidney failure. In addition to its high renal expression, RNLS is also detectable in the heart, skeletal muscle, and other tissues, underscoring its broader endocrine role in maintaining cardiovascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural and biochemical studies have further refined our understanding of RNLS’s catalytic mechanism. Although initial reports emphasized the oxidation of catecholamines, new evidence demonstrates that RNLS adopts a Rossmann‐fold–based structure with an active site that is highly solvent exposed, and it appears to preferentially oxidize specific isomeric forms of reduced nicotinamide adenine dinucleotides – namely 2‐ and 6–dihydroNAD(P)H. This enzymatic activity, which proceeds via reduction of the bound FAD cofactor and subsequent electron transfer to oxygen, suggests that RNLS may help eliminate inhibitory “off‐pathway” dinucleotide isomers and thereby sustain normal primary metabolic dehydrogenase activity. In addition, insights into RNLS’s secretion mechanisms have raised the possibility that its processing and extracellular actions are more complex than previously thought."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its catalytic functions, RNLS also acts as a cytokine that can trigger intracellular survival signals via the PI3K/AKT and MAPK pathways. This signaling activity is thought to underlie its cytoprotective effects observed in diverse experimental settings – from attenuation of ischemia‐reperfusion injury and nephrotoxicity to modulation of myocardial and even tumor cell survival. Such dual functionality, encompassing both enzyme activity and receptor‐mediated pro‐survival signaling, suggests that RNLS contributes to tissue protection and repair processes in addition to regulating hemodynamics. Moreover, altered RNLS signaling has been linked to conditions such as preeclampsia and may influence the pathogenesis of cardiovascular and metabolic diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging data also indicate that RNLS expression extends beyond traditional cardiovascular and metabolic tissues. It is notably present in reproductive and steroidogenic organs – including oocytes, granulosa and luteal cells in the ovary and spermatogenic cells in the testis – where it may influence germ cell maturation and hormonal regulation. These findings, together with ongoing studies of RNLS gene regulation and polymorphic variation, underscore the enzyme’s multifaceted roles and hint at novel contributions to human physiology and disease that warrant further investigation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jianchao Xu, Guoyong Li, Peili Wang, et al. 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