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In order to elucidate the mechanisms of post-exercise acute renal failure, one of the complications of hereditary renal hypouricemia, we have targeted the mouse Slc22a12 gene by the exchange of exons 1-4 with pMC1neo-polyA. The knockout mice revealed no gross anomalies. The concentration ratio of urinary urate/creatinine of the knockout mice was significantly higher than that of wildtype mice, indicating an attenuated renal reabsorption of urate. The plasma levels of urate were around 11 μM and were similar among the genotypes. Although the fractional excretion of urate of knockout mice was tend to higher than that of wildtype mice, the urate reabsorption ability remained in the kidney of knockout mice, indicating a urate reabsorptive transporter other than Urat1. [ABSTRACT FROM AUTHOR]

The use of collagen in cell cultures promotes cell proliferation and differentiation, and it has been commercialized. In this study, we separated and purified collagen from adipose tissue discarded during liposuction and prepared collagen-coated dishes. After collagen was identified from human adipose tissue, type identification and quantification were performed using SDS-PAGE and FPLC. Collagen type I was used to coat culture dishes. Human skin fibroblasts and human adipose tissue-derived stem cells were seeded at a density of 2.5 × 105 cells/ml on prepared dishes at a collagen concentration of 3 mg/ml and cultured for 7 days. Cell viability was then measured and analyzed. The WST-1 assay was used to evaluate the results. The amount of collagen in 300 g of adipose tissue was 25.5 mg for type I, 41.4 mg for type III, 10.6 mg for type IV, 6.5 mg for type V and 15 mg for type VI. The highest rates were observed for adipose stem cells cultured on human adipose tissue-derived collagen-coated dishes. In cell cultures, cell affinity was higher when cells and the substrate used were of the same origin, and affinity was stronger when the tissue of origin was the same., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Global cerebral ischemia (GCI) caused by clinical conditions such as cardiac arrest leads to delayed neuronal death in the hippocampus, resulting in physical and mental disability. However, the mechanism of delayed neuronal death following GCI remains unclear. To elucidate the mechanism, we performed a metabolome analysis using a mouse model in which hypothermia (HT) during GCI, which was induced by the transient occlusion of the bilateral common carotid arteries, markedly suppressed the development of delayed neuronal death in the hippocampus after reperfusion. Fifteen metabolites whose levels were significantly changed by GCI and 12 metabolites whose levels were significantly changed by HT were identified. Furthermore, the metabolites common for both changes were narrowed down to two, adenosine monophosphate (AMP) and xanthosine monophosphate (XMP). The levels of both AMP and XMP were found to be decreased by GCI, but increased by HT, thereby preventing their decrease. In contrast, the levels of adenosine, inosine, hypoxanthine, xanthine, and guanosine, the downstream metabolites of AMP and XMP, were increased by GCI, but were not affected by HT. Our results may provide a clue to understanding the mechanism by which HT during GCI suppresses the development of delayed neuronal death in the hippocampus., (© 2024. The Author(s).)

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase. In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins., (© 2023. The Author(s).)

Bovine-derived collagen gel has been used in the medical field as an injection formulation, but there are concerns about cross-infection such as bovine spongiform encephalopathy. In this study, we attempted to use fish as a safe alternative to bovine collagen., Objective: Fish collagen has not been used in clinical settings, so we examined its potential by comparing its properties with those of bovine-derived collagen., Methods: Collagen was extracted from the ventral skin of flatfish. It was cross-linked with 1%, 3%, or 5% of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and treated with 1%, 5%, or 10% of lactose. Hydroxyproline contents and Young's modulus (elasticity) were measured. In addition, these were injected under the back of BALB/c nude mice and the amount of hydroxyproline was observed. Histological examination of the samples was also conducted., Results: The amount of hydroxyproline in fish collagen was 3.3 ± 0.3 μg/mg. The 3% collagen gel treated with 5% EDC and 5% lactose had the highest Young's modulus and was closest to the bovine-derived collagen injection formulation. When injected into mice, it was retained in vivo for about 90 days., Conclusions: Fish collagen has a low denaturation temperature and is unstable and easily biodegrades in mammalian organisms. However, it is possible to approach the properties of conventional mammalian collagen by cross-linking and lactose treatment, suggesting that fish collagen can be used as a scaffold for cells in regenerative medicine., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1 - Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs)., Methods: The novel Urat1 - Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters., Results: Urat1 - Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1 - Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na + -K + -ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI., Conclusions: Urat1 - Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1 β via NLRP3 inflammasome signaling and Na + -K + -ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI., (Copyright © 2022 by the American Society of Nephrology.)

For the practical application of triplet-triplet annihilation-based photon upconversion (TTA-UC), the development of rigid, transparent, air-stable, and moldable materials with a high TTA-UC efficiency remains a challenging issue. In addition to the noncovalent introduction of ionic liquid emitters into the epoxy network, we covalently introduce emitters with polymerization sites to increase the emitter concentration to 35.6 wt %. A TTA-UC quantum yield Φ UC of 5.7% (theoretical maximum: 50%) or a TTA-UC efficiency η UC of 11.4% (theoretical maximum: 100%) is achieved, which is the highest value ever achieved for a rigid polymer material. More importantly, the high emitter concentration speeds up the triplet diffusion and suppresses the back energy transfer from the emitter to sensitizer so that the sensitized emitter triplet can be effectively utilized for TTA. The generality of our finding is also confirmed for epoxy resins of similar emitter unit concentrations without the ionic liquid. This work provides important design guidelines for achieving highly efficient TTA-UC in rigid solid materials, which has been very difficult to achieve in the past. Furthermore, the solid-state TTA-UC exhibits high air stability, reflecting the high oxygen barrier performance of epoxy resins. The high moldability of epoxy resins allows the construction of upconversion materials with complex geometries at nano- to macroscopic scales.

LLC-PK1 renal cells show Na + -dependent and Na + -independent hypoxanthine uptake. While the latter is inhibited by adenine, neither are inhibited by xanthine. In rats, intestinal Na + -dependent hypoxanthine transporter Slc23a4 is not expressed in the kidney, and its action is inhibited by xanthine. This study aimed to clone Slc23a4 -paralog SLC23A3 from the human kidney and investigate its hypoxanthine transport activity. We observed Na + -dependent 10 nM [ 3 H]-hypoxanthine uptake in SLC23A3 RNA-injected Xenopus oocytes. Moreover, 100 μM xanthine did not inhibit Na + -independent 300 nM [ 3 H]-hypoxanthine uptake, whereas 100 μM adenine did. These results confirm that SLC23A3 is a hypoxanthine transporter in the human kidney.

Renal hypouricemia (RHUC) is a hereditary disease that presents with increased renal urate clearance and hypouricemia due to genetic mutations in the urate transporter URAT1 or GLUT9 that reabsorbs urates in the renal proximal tubule. Exercise-induced acute kidney injury (EIAKI) is known to be a complication of renal hypouricemia. In the skeletal muscle of RHUC patients during exhaustive exercise, the decreased release of endothelial-derived hyperpolarization factor (EDHF) due to hypouricemia might cause the disturbance of exercise hyperemia, which might increase post-exercise urinary urate excretion. In the kidneys of RHUC patients after exhaustive exercise, an intraluminal high concentration of urates in the proximal straight tubule and/or thick ascending limb of Henle's loop might stimulate the luminal Toll-like receptor 4-myeloid differentiation factor 88-phosphoinositide 3-kinase-mammalian target of rapamycin (luminal TLR4-MyD88-PI3K-mTOR) pathway to activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and may release interleukin-1β (IL-1β), which might cause the symptoms of EIAKI.

It remains challenging to achieve efficient and air-stable photon upconversion (UC) in rigid, technologically valuable transparent films. Here, we report the first example of epoxy resins that show an air-stable and efficient triplet-triplet annihilation (TTA)-based UC. Epoxy resins are thermally cross-linked polymers widely used as coating and sealing materials in actual devices. To achieve efficient TTA-UC in rigid epoxy films, it is essential to execute both the triplet sensitization and triplet exciton diffusion processes without relying on molecular diffusion. This requires homogeneously dispersing emitter molecules without aggregation in three-dimensionally cross-linked rigid polymer networks at a high concentration (ca. 1000 mM) such that the inter-emitter distance is less than 1 nm, where dexter energy transfer can occur. This difficult requirement is solved by employing an ionic liquid emitter that consists of 9,10-diphenylanthracene sulfonate and lipophilic phosphonium ions bearing long alkyl chains. The obtained epoxy resins show a high TTA-UC efficiency (η UC = 3.8%) and low threshold excitation intensity ( I th = 40 mW cm -2 ) in air. These UC parameters are achieved by virtue of a very high sensitizer-to-emitter triplet energy-transfer efficiency (92.8%) and a significantly long emitter triplet lifetime (17.8 ms) that reflect the high emitter concentration and the rigid chromophore environment, respectively. The bulk transparent upconverting resins can be prepared in air and function in air, which opens a new avenue toward a wide range of real-world applications.

While many studies have been done on triplet-triplet annihilation-based photon upconversion (TTA-UC) to produce visible light with high efficiency, the efficient TTA-UC from visible to UV light, despite its importance for a variety of solar and indoor applications, remains a challenging task. Here, we report the highest visible-to-UV TTA-UC efficiency of 20.5 % based on the discovery of an excellent UV emitter, 1,4-bis((triisopropylsilyl)ethynyl)naphthalene (TIPS-Nph). TIPS-Nph is an acceptor with desirable features of high fluorescence quantum yield and high singlet generation efficiency by TTA. TIPS-Nph has a low enough triplet energy level to be sensitized by Ir(C6) 2 (acac), a superior donor that does not quench UV emission. The combination of TIPS-Nph and Ir(C6) 2 (acac) realizes the efficient UV light production even with weak light sources such as an AM 1.5 solar simulator and room LEDs., (© 2020 Wiley-VCH GmbH.)

Thyroid hormones (THs) have been suggested to play an important role in both physiological and pathological events in the central nervous system. Hypothyroidism, which is characterized by low levels of serum THs, has been associated with aggravation of ischemic neuronal injuries in stroke patients. We hypothesized that administration of T 3 , the main active form of THs, may attenuate the ischemic neuronal injuries. In mice, global cerebral ischemia (GCI), which is induced by transient occlusion of the bilateral common carotid artery, causes neuronal injuries by inducing neuronal death and activating inflammatory responses after reperfusion in the hippocampus. In this study, we examined the effect of T 3 administration on DNA fragmentation induced by neuronal death and the activation of inflammatory cells such as astrocytes and microglia in the hippocampus following GCI. The content of nucleosomes generated by DNA fragmentation in the hippocampus was increased by GCI and further increased by T 3 administration. The protein expression levels of glial fibrillary acidic protein (GFAP), an astrocytic marker, and Ionized calcium binding adaptor protein 1 (Iba1), a microglial marker, in the hippocampus were also increased by GCI and further increased by T 3 administration. The levels of T 3 in both the serum and hippocampus were elevated by T 3 administration. Our results indicate that T 3 administration aggravates GCI-reperfusion injury in mice. There may be an increased risk of aggravation of ischemic stroke by the excessive elevation of T 3 levels during the drug treatment of hypothyroidism.

The volume, composition, and movement of the cerebrospinal fluid (CSF) are important for brain physiology, pathology, and diagnostics. Nevertheless, few studies have focused on the main structure that produces CSF, the choroid plexus (CP). Due to the presence of monocarboxylate transporters (MCTs) in the CP, changes in blood and brain lactate levels are reflected in the CSF. A lactate receptor, the hydroxycarboxylic acid receptor 1 (HCA 1 ), is present in the brain, but whether it is located in the CP or in other periventricular structures has not been studied. Here, we investigated the distribution of HCA 1 in the cerebral ventricular system using monomeric red fluorescent protein (mRFP)-HCA 1 reporter mice. The reporter signal was only detected in the dorsal part of the third ventricle, where strong mRFP-HCA 1 labeling was present in cells of the CP, the tela choroidea, and the neuroepithelial ventricular lining. Co-labeling experiments identified these cells as fibroblasts (in the CP, the tela choroidea, and the ventricle lining) and ependymal cells (in the tela choroidea and the ventricle lining). Our data suggest that the HCA 1 -containing fibroblasts and ependymal cells have the ability to respond to alterations in CSF lactate in body-brain signaling, but also as a sign of neuropathology (e.g., stroke and Alzheimer's disease biomarker).

Recent genome-wide association studies have revealed some genetic loci associated with serum uric acid levels and susceptibility to gout/hyperuricemia which contain potential candidates of physiologically important urate transporters. One of these novel loci is located upstream of SGK1 and SLC2A12 , suggesting that variations in these genes increase the risks of hyperuricemia and gout. We herein focused on SLC2A12 encoding a transporter, GLUT12, the physiological function of which remains unclear. As GLUT12 belongs to the same protein family as a well-recognized urate transporter GLUT9, we hypothesized that GLUT12 mediates membrane transport of urate. Therefore, we conducted functional assays and analyzed Glut12 knockout hyperuricemia model mice, generated using the CRISPR-Cas9 system. Our results revealed that GLUT12 acts as a physiological urate transporter and its dysfunction elevates the blood urate concentration. This study provides insights into the deeper understanding of the urate regulatory system in the body, which is also important for pathophysiology of gout/hyperuricemia., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The oxidant/antioxidant imbalance plays a pivotal role in the lung. Uric acid (UA), an endogenous antioxidant, is highly present in lung tissue, however, its impact on lung function under pathophysiological conditions remains unknown. In this work, pharmacological and genetic inhibition of UA metabolism in experimental mouse models of acute and chronic obstructive pulmonary disease (COPD) revealed that increased plasma UA levels improved emphysematous phenotype and lung dysfunction in accordance with reduced oxidative stress specifically in female but not in male mice, despite no impact of plasma UA induction on the pulmonary phenotypes in nondiseased mice. In vitro experiments determined that UA significantly suppressed hydrogen peroxide (H 2 O 2 )-induced oxidative stress in female donor-derived primary human bronchial epithelial (NHBE) cells in the absence of estrogen, implying that the benefit of UA is limited to the female airway in postmenopausal conditions. Consistently, our clinical observational analyses confirmed that higher blood UA levels, as well as the SLC2A9/GLUT9 rs11722228 T/T genotype, were associated with higher lung function in elderly human females. Together, our findings provide the first unique evidence that higher blood UA is a protective factor against the pathological decline of lung function in female mice, and possibly against aging-associated physiological decline in human females., Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Purine metabolism in mice and human differ in terms of uricase (Uox) activity as well as hypoxanthine phosphoribosyltransferase (HPRT) activity. The aim of this study was the establishment of high HPRT activity-Uox knockout (KO) mice as a novel hyperuricaemic model. Then to investigate the effects of purine-type xanthine dehydrogenase (XDH) inhibitor, allopurinol, and non-purine-type XDH inhibitor, topiroxostat, on purine metabolism., Experimental Approach: A novel hyperuricaemic mouse model was established by mating B6-ChrXC MSM mice with uricase KO mice. The pharmacological effects of allopurinol and topiroxostat were explored by evaluating urate, hypoxanthine, xanthine and creatinine in the plasma and urine of these model mice. Furthermore, we analysed the effect of both drugs on erythrocyte hypoxanthine phosphoribosyltransferase activity., Key Results: Plasma urate level and urinary urate/creatinine ratio significantly decreased after administration of allopurinol 30 mg·kg -1 or topiroxostat 1 mg·kg -1 for 7 days. The urate-lowering effect was equivalent for allopurinol and topiroxostat. However, the urinary hypoxanthine/creatinine ratio and xanthine/creatinine ratio after treatment with topiroxostat were significantly lower than for allopurinol. In addition, the urinary oxypurine/creatinine ratio was significantly lowered after treatment with topiroxostat, but allopurinol elicited no such effect. Furthermore, allopurinol inhibited mouse erythrocyte hypoxanthine phosphoribosyltransferase, while topiroxostat did not., Conclusions and Implications: High hypoxanthine phosphoribosyltransferase activity- uricase KO mice were established as a novel hyperuricaemic animal model. In addition, topiroxostat, a non-purine-type xanthine dehydrogenase inhibitor, elicited a potent plasma urate-lowering effect. However, unlike allopurinol, topiroxostat did not perturb the salvage pathway, resulting in lowered total oxypurine excretion., (© 2020 The British Pharmacological Society.)

Objective: Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine., Conclusions: The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

Although xanthinuria is nonfatal in human, xanthine oxidoreductase knockout ( Xor- KO) mice have only a short lifespan. Hypoxanthine phosphoribosyltransferase activity (HPRT) in human and wild mice is higher than in laboratory mice. The aim of this study was to investigate the underlying mechanisms that give rise to the longer lifespan of high-HPRT/ Xor- KO mice. Before Xor -KO mice die, urinary excretion of hypoxanthine increased with a corresponding decrease in excretion of xanthine. The switch of excretion from xanthine to hypoxanthine might be a cause of death for Xor- KO mice, suggesting inhibition of NAD + -dependent IMP dehydrogenase. Because hypoxanthine inhibits the synthesis of nicotinamide mononucleotide (NMN), a precursor of NAD + , the accumulation of hypoxanthine in Xor- KO mice may cause a depletion in the levels of NAD + . Moreover, urinary excretion of urate in high-HPRT/Uox-KO/ Xor- KO mice means urate derived from gut microbiota is absorbed by the intestine. Likewise, over excretion of oxypurine in mice may be caused by intestinal absorption of oxypurine. For NAD + replenishment, oral supplementation with 1% L-tryptophan, an alternative precursor of NAD + , resulted in a recovery of body weight gain in high-HPRT/Uox-KO/ Xor- KO mice. In conclusion, the death of Xor -KO mice by renal failure seems to be caused by a depletion in NAD + levels due to the intracellular accumulation of hypoxanthine. NAD + replenishment by oral supplementation of NMN or tryptophan was complicated by the effect of gut microbiota and failed to rescue high-HPRT/ Xor -KO mice. The attenuation of intestinal absorption of oxypurines seems to be necessary to avoid hypoxanthine accumulation and over excretion of oxypurine.

To elucidate roles of the intestine in uric acid (UA) metabolism, we examined ABCG2 expression, tissue UA content and xanthine oxidoreductase (XOR) activity in different intestinal segments. Male SD rats were assigned to control group or oxonic acid-induced hyperuricemia (HUA) group. In control rats, ABCG2 was present both in villi and crypts in each segment. Tissue UA content and XOR activity were relatively high in duodenum and jejunum. However, in HUA rats, tissue UA content was significantly elevated in the ileum, whereas it remained unaltered in other segments. Moreover, ABCG2 expression in the HUA group was upregulated both in the villi and crypts of the ileum. These data indicate that the ileum may play an important role in the extra-renal UA excretion.

Molecular self-assembly is a powerful means to construct nanoscale materials with advanced photophysical properties. Although the protection of the photo-excited states from oxygen quenching is a critical issue, it still has been in an early phase of development. In this work, we demonstrate that a simple and typical molecular design for aqueous supramolecular assembly, modification of the chromophoric unit with hydrophilic oligo(ethylene glycol) chains and hydrophobic alkyl chains, is effective to avoid oxygen quenching of triplet-triplet annihilation-based photon upconversion (TTA-UC). While a TTA-UC emission is completely quenched when the donor and acceptor are molecularly dispersed in chloroform, their aqueous co-assemblies exhibit a clear upconverted emission in air-saturated water even under extremely low chromophore concentrations down to 40 μm. The generalization of this nano-encapsulation approach offers new functions and applications using oxygen-sensitive species for supramolecular chemistry., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the "MINDS Manual for Guideline Development" methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG's unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC.

While dynamic nuclear polarization based on photoexcited triplet electrons (triplet-DNP) has the potential to hyperpolarize nuclear spins of target substrates in the low magnetic field at room temperature, there has been no triplet-DNP system offering structural rigidity and substrate accessibility. Here, we report the first example of triplet-DNP of nanoporous metal-organic frameworks. Accommodation of a carboxylate-modified pentacene derivative in a partially deuterated ZIF-8 (D-ZIF-8) results in a clear 1 H NMR signal enhancement over thermal equilibrium.

It is pivotal to achieve efficient triplet-triplet annihilation based photon upconversion (TTA-UC) in the solid-state for enhancing potentials of renewable energy production devices. However, the UC efficiency of solid materials is largely limited by low fluorescence quantum yields that originate from the aggregation of TTA-UC chromophores and also by severe back energy transfer from the acceptor singlet state to the singlet state of the triplet donor in the condensed state. In this work, to overcome these issues, we introduce a highly fluorescent singlet energy collector as the third component of donor-doped acceptor crystalline films, in which dual energy migration, i.e., triplet energy migration for TTA-UC and succeeding singlet energy migration for transferring energy to a collector, takes place. To demonstrate this scheme, a highly fluorescent singlet energy collector was added as the third component of donor-doped acceptor crystalline films. An anthracene-based acceptor containing alkyl chains and a carboxylic moiety is mixed with the triplet donor Pt(II) octaethylporphyrin (PtOEP) and the energy collector 2,5,8,11-tetra- tert-butylperylene (TTBP) in solution, and simple spin-coating of the mixed solution gives acceptor films of nanofibrous crystals homogeneously doped with PtOEP and TTBP. Interestingly, delocalized singlet excitons in acceptor crystals are found to diffuse effectively over the distance of ∼37 nm. Thanks to this high diffusivity, only 0.5 mol % of doped TTBP can harvest most of the singlet excitons, which successfully doubles the solid-state fluorescent quantum yield of acceptor/TTBP blend films to 76%. Furthermore, since the donor PtOEP and the collector TTBP are separately isolated in the nanofibrous acceptor crystals, the singlet back energy transfer from the collector to the donor is effectively avoided. Such efficient singlet energy collection and inhibited back energy transfer processes result in a large increase of UC efficiency up to 9.0%, offering rational design principles toward ultimately efficient solid-state upconverters.

A method for synthesizing coordination nanofibers by extracting the structural motifs of metal-organic frameworks (MOFs) is demonstrated. In these soluble nanofibers, multiple chromophores with largely different sizes and shapes can be arranged at desired compositions, and excited triplet energy migrates among the densely assembled chromophore arrays, showing an efficient photon upconversion even at very low concentration.

Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate how diabetes and hypoglycemic agents alter the levels of renal urate transporters. In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA were increased, suggesting that tubular handling of UA is altered in this model. In the membrane fraction of the kidney, the expression of urate transporter 1 (URAT1) was significantly decreased, whereas that of ATP-binding cassette subfamily G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Administration of insulin to the diabetic rats decreased UA excretion and alleviated UA transporter-level changes, while sodium glucose cotransporter 2 inhibitor (SGLT2i) ipragliflozin did not change renal UA handling in this model. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received insulin and separately, ipragliflozin. Insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. In contrast, the SGLT2i did not alter URAT1 or ABCG2 levels, although blood glucose levels were similarly reduced. Furthermore, we found that insulin significantly increased endogenous URAT1 levels in the membrane fraction of NRK-52E cells, the kidney epithelial cell line, demonstrating the direct effects of insulin on renal UA transport mechanisms. These results suggest a previously unrecognized mechanism for the anti-uricosuric effects of insulin and provide novel insights into the renal UA handling in the diabetic state., (Copyright © 2017 the American Physiological Society.)

Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100 mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0 mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT-1-positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8-hydroxy-2-deoxyguanosine (8-OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12 mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objective: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific., Methods: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study., Results: In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10 -8 ): urate transporter genes ( SLC22A12 and SLC17A1 ) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10 -8 )., Conclusions: Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2'-deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state., Competing Interests: The authors have declared that no competing interests exist.

Background: Uric acid (UA) is known to exert neuroprotective effects in the brain. However, the mechanism of UA regulation in the brain is not well characterized. In our previous study, we described that the mouse urate transporter URAT1 is localized to the cilia and apical surface of ventricular ependymal cells. To further strengthen the hypothesis that UA is transported transcellularly at the ependymal cells, we aimed to assess the distribution of other UA transporters in the murine brain., Methods: Immunostaining and highly-sensitive in situ hybridization was used to assess the distribution of UA transporters: GLUT9/URATv1, ABCG2, and URAT1., Results: Immunostaining for GLUT9 was observed in ependymal cells, neurons, and brain capillaries. Immunostaining for ABCG2 was observed in the choroid plexus epithelium and brain capillaries, but not in ependymal cells. These results were validated by in situ hybridization., Conclusions: We propose that given their specific expression patterns in ependymal, choroid plexus epithelial, and brain capillary endothelial cells in this study, UA may be transported by these UA transporters in the murine brain. This may provide a novel strategy for targeted neuroprotection.

Renal hypouricemia (RHUC) is a hereditary disease characterized by a low level of plasma urate but with normal urinary urate excretion. RHUC type 1 is caused by mutations of the urate transporter URAT1 gene (SLC22A12). However, the plasma urate levels of URAT1 knockout mice are no different from those of wild-type mice. In the present study, a double knockout mouse, in which the URAT1 and uricase (Uox) genes were deleted (Urat1-Uox-DKO), were used as an experimental animal model of RHUC type 1 to investigate RHUC and excise-induced acute kidney injury (EIAKI). Mice were given a variable content of allopurinol for one week followed by HPLC measurement of urate and creatinine concentrations in spot urine and blood from the tail. The urinary excretion of urate in Urat1-Uox-DKO mice was approximately 25 times higher than those of humans. With allopurinol, the plasma urate levels of Urat1-Uox-DKO mice were lower than those of Uox-KO mice. There were no differences in the urinary urate excretions between Urat1-Uox-DKO and Uox-KO mice administered with 9 mg allopurinol /100 g feed. In the absence of allopurinol, plasma creatinine levels of some Urat1-Uox-DKO mice were higher than those of Uox-KO mice. Consequently, hypouricemia and normouricosuria may indicate that the Urat1-Uox-DKO mouse administered with allopurinol may represent a suitable animal model of RHUC type 1. Urat1-Uox-DKO mice without allopurinol exhibited acute kidney injury, thus providing additional benefit as a potential animal model for EIAKI. Finally, our data indicate that allopurinol appears to provide prophylactic effects for EIAKI.