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Accumulating evidence suggests that excess fructose uptake induces metabolic syndrome and kidney injury. Here, we primarily investigated the influence of catalpol on fructose-induced renal inflammation in mice and explored its potential mechanism. Treatment with catalpol improved insulin sensitivity and hyperuricemia in fructose-fed mice. Hyperuricemia induced by high-fructose diet was associated with increases in the expressions of urate reabsorptive transporter URAT1 and GLUT9. Treatment with catalpol decreased the expressions of URAT1 and GLUT9. Futhermore, treatment with catalpol ameliorated renal inflammatory cell infiltration and podocyte injury, and these beneficial effects were associated with inhibiting the production of inflammatory cytokines including IL-1β, IL-18, IL-6 and TNF-α. Moreover, fructose-induced uric acid triggers an inflammatory response by activiting NLRP3 inflammasome, which then processes pro-inflammatory cytokines. Treatment with catalpol could inhibit the activation of NLRP3 inflammasome as well. Additionally, TLR4/MyD88 signaling was activated in fructose-fed mice, while treatment with catalpol inhibited this activation along with promoting NF-κB nuclear translocation in fructose-fed mice. Thus, our study demonstrated that catalpol could ameliorate renal inflammation in fructose-fed mice, attributing its beneficial effects to promoting uric acid excretion and inhibit the activation of TLR4/MyD88 signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Numerous epidemiological studies have demonstrated that hyperuricemia (HUA) is a risk factor for renal diseases and renal fibrosis. Dietary patterns can influence serum urate levels and hyperuricemic nephropathy (HN). NLRP3 inflammasomes play a crucial role in various inflammatory responses and contribute to HN progression. Chloroquine (CQ) is an anti-inflammatory and disease-modifying anti-rheumatic drug (DMARD) utilized in treating autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this study, we examined the effects and underlying mechanisms of CQ in a high-fat-diet (HFD) exacerbated mouse model of HN. C57BL/6 mice were randomized into either a control group or an HN group (induced by adenine/potassium oxonate treatment), followed by a normal diet or HFD, with or without CQ treatment. Our findings revealed that the HN group exhibited elevated serum levels of blood urea nitrogen (BUN) and creatinine compared to the control group. Additionally, the HN + HFD group displayed increased serum levels of uric acid, BUN, and creatinine relative to the control + HFD group. Moreover, the HFD exacerbated renal uric acid crystal deposition and fibrosis in HN mice compared to a normal diet. CQ ameliorated renal dysfunction, as evidenced by reduced serum creatinine levels, renal fibrosis, and renal tubular injury scores, and significantly decreased NLRP3, ASC, caspase-1, and IL-1β levels in HN mice. These findings suggest that CQ inhibits the activation of NLRP3 inflammasomes and may serve as a potential therapeutic strategy for HN treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mesenchymal stem cells (MSCs), due to their multi-directional differentiation, paracrine and immunomodulation potentials, and the capacity of homing to target organ, have been reported to facilitate regeneration and repair of kidney and improve kidney function in acute or chronic kidney injury. The present study was aimed to evaluate whether MSCs could have a protective effect in hyperuricemic nephropathy (HN) and the underlying mechanisms. A rat HN model was established by oral administration of a mixture of potassium oxonate (PO, 1.5 g/kg) and adenine (Ad, 50 mg/kg) daily for 4 weeks. For MSCs treatment, MSCs (3 × 10 6 cells/kg per week) were injected via tail vein from the 2nd week for 3 times. The results showed that along with the elevated uric acid (UA) in HN rats, creatinine (CREA), blood urea nitrogen (BUN), microalbuminuria (MAU) and 24-hour urinary protein levels were significantly increased comparing with the normal control rats, while decreased after MSCs treatment. Moreover, the mRNA levels of inflammation and fibrosis-related gene were reduced in UA + MSCs group. Consistently, hematoxylin-eosin (HE) staining results showed the destruction of kidney structure and fibrosis were significantly alleviated after MSCs administration. Similarly, in vitro, NRK-52Es cells were treated with high concentration UA (10 mg/dL) in the presence of MSCs, and we found that MSCs co-culture could inhibited UA-induced cell injury, characterized as improvement of cell viability and proliferation, inhibition of apoptosis, inflammation, and fibrosis. Collectively, MSCs treatment could effectively attenuate UA-induced renal injury, and thus it might be a potential therapy to hyperuricemia-related renal diseases., (Copyright © 2021. Published by Elsevier B.V.)

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD). Excessive uric acid (UA) level in the blood leads to hyperuricemic nephropathy (HN), which is characterized by glomerular hypertension, arteriolosclerosis and tubulointerstitial fibrosis. Fatty acid binding protein 4 (FABP4) is a potential mediator of inflammatory responses which contributes to renal interstitial fibrosis. However, the roles of FABP4 in HN remains unknown. In the study, a mouse model of HN induced by feeding a mixture of adenine and potassium oxonate, severe kidney injury and interstitial fibrosis, as well as the increased kidney-expressed FABP4 protein level were evident, accompanied by the activation of inflammatory responses. Oral administration of BMS309403, a highly selective FABP4 inhibitor, improved renal dysfunction, inhibited the mRNA level of KIM-1 and NGAL, as well as reduced the expression of proinflammatory cytokines and fibrotic proteins in the injured kidneys. BMS309403 treatment also inhibited the FABP4 activity and further suppressed the activation of JAK2-STAT3 and NF-kB P65 signaling pathways in the hyperuricemia-injured kidneys and UA-stimulated human tubular epithelial (HK-2) cells, respectively. In summary, our study for the first time demonstrated that FABP4 played a crucial role in kidney inflammation and fibrosis via the regulation of JAK2-STAT3 and NF-kB P65 pathways in HN mice. The results suggested that FABP4 inhibition might be a promising therapeutic strategy for HN., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hyperuricemia is becoming a serious public health issue, which is highly influenced by environmental factors, although there is still controversial information on the potential influence of the exposure to Persistent Toxic Substances (PTSs) in the general population. In this study we aimed to assess the association. PTS exposure with uric acid homeostasis in a sample of the Spanish population. Participants were recruited during 2009-2010 in all the main geographical areas of Spain. Exposure to 34 PTSs was estimated by chemical analyses of serum levels of 6 Polychlorinated Biphenyls (PCBs, n = 950), 13 Organochlorine Pesticides (OCPs, n = 453), 6 Perfluoroalkyl Substances (PFAs, n = 755), 7 Polybrominated Diphenyl Ethers (PBDEs, n = 365), urinary Cadmium (n = 926), and Lead in whole blood (n = 882). The two study outcomes were defined as the prevalence of hyperuricemia in the study population and uric acid levels, the latter only in individuals with no previous diagnosis of hyperuricemia. Statistical analyses were performed by means of binomial logistic regression and linear regression, and mixture effects were screened using Weighted Quantile Sum Regression (WQS). Serum concentrations of γ-HCH, o,p´-DDE, PCB-138, PCB-153, PFOA, and urinary Cadmium were associated with an increased risk of hyperuricemia, while PBDE-153 showed an inverse association with the effect. Furthermore, exposure to Cadmium, PCB-138, and to PCB-153 was positively associated with uric acid levels. Results were consistent after lipid adjustment or standardization. WQS analyses revealed a major contribution of PCB-153 within the PCB mixture on both the risk of hyperuricemia and uric acid levels. Sensitivity analyses were performed by adjusting for dietary habits, fasting glucose and estimated glomerular filtration rate. Overall, we found novel associations between human exposure to mixtures of PTSs and disturbances in uric acid homeostasis. However, we cannot completely rule out potential residual confounding effect or reversed-causality related to the cross-sectional design., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hyperuricemia is a risk factor for not only gout, but also to a variety of disorders that affect the vital organ systems of the human body. The xanthine oxidase (XO) is the key enzyme in the production of uric acid and its inhibition can inhibit hyperuricemia. Although, XO inhibitor allopurinol is widely prescribed antigout agent but its use is not without any side effects. Previously, we described the synthesis of four novel thiadiazolopyrimidin-5-one analogues as effective XO inhibitors and molecular docking studies also confirmed this. When these analogues were tested in potassium oxonate treated rats, their serum uric acid and creatinine levels were dropped significantly from 4.85±0.03 mg/dl to 1.21±0.01 mg/dl and 0.92±0.02 mg/dl to 0.40±0.02 mg/dl respectively. Among the pyrimidine analogues tested, 6a was most potent. Histological examinations of both liver and kidney tissues exhibited severe necrosis in oxonate treated rats and pyrimidine analogues could significantly attenuate this with a correlative inhibitory profile of hepatic XO from the same rats. Our results demonstrate antihyperuricemic effect of novel thiadiazolopyrimidin-5-one analogues in oxonate treated rats, which can be further explored not only as antigout therapeutics but also in other systems where hyperuricemia is the driving cause of the disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There is very limited information on the association between arsenic and serum uric acid levels or gout. The aim of this study was to investigate the association of arsenic with hyperuricemia and gout in US adults., Methods: A cross-sectional study was conducted in 5632 adults aged 20years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2010 with determinations of serum uric acid and urine total arsenic and dimethylarsinate (DMA). Hyperuricemia was defined as serum uric acid higher than 7.0mg/dL for men and 6.0mg/dL for women. Gout was defined based on self-reported physician diagnosis and medication use., Results: After adjustment for sociodemographic factors, comorbidities and arsenobetaine levels, the increase in the geometric means of serum uric acid associated with one interquartile range increase in total arsenic and DMA levels was 3% (95% CI 2-5) and 3% (2-5), respectively, in men and 1% (0-3) and 2% (0-4), respectively, in women. In men, the adjusted odds ratio for hyperuricemia comparing the highest to lowest quartiles of total arsenic was 1.84 (95% CI, 1.26-2.68) and for DMA it was 1.41 (95% CI, 1.01-1.96). The corresponding odds ratios in women were 1.26 (0.77, 2.07) and 1.49 (0.96, 2.31), respectively. The odds ratio for gout comparing the highest to lowest tertiles was 5.46 (95% CI, 1.70-17.6) for total arsenic and 1.98 (0.64-6.15) for DMA among women older than 40years old. Urine arsenic was not associated with gout in men., Conclusion: Low level arsenic exposures may be associated with the risk of hyperuricemia in men and with the prevalence of gout in women. Prospective research focusing on establishing the direction of the relationship among arsenic, hyperuricemia, and gout is needed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Nuciferine, a major aporphine alkaloid of the leaves of Nelumbo nucifera, was found to decrease serum urate levels and improved kidney function, as well as inhibited system and renal interleukin-1β (IL-1β) secretion in potassium oxonate-induced hyperuricemic mice. Furthermore, nuciferine reversed expression alteration of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), and organic cation/carnitine transporters 1/2 (OCTN1/2) in hyperuricemic mice. More importantly, nuciferine suppressed renal activation of Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB (TLR4/MyD88/NF-κB) signaling and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome to reduce serum and renal IL-1β levels in hyperuricemic mice with renal inflammation reduction. The anti-inflammatroy effect of nuciferine was also confirmed in human proximal renal tubular epithelial cells (HK-2 cells) incubated with 4mg/dl uric acid for 24h. This study firstly reported the anti-hyperuricemic and anti-inflammatory effects of nuciferine by regulating renal organic ion transporters and inflammatory signaling in hyperuricemia. These results suggest that a dietary supplement of nuciferine rich in lotus leaf may be potential for the prevention and treatment of hyperuricemia with kidney inflammation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

High fructose intake causes metabolic syndrome, being an increased risk of chronic kidney disease development in humans and animals. In this study, we examined the influence of betaine on high-fructose-induced renal damage involving renal inflammation, insulin resistance and lipid accumulation in rats and explored its possible mechanisms. Betaine was found to improve high-fructose-induced metabolic syndrome including hyperuricemia, dyslipidemia and insulin resistance in rats with systemic inflammation. Betaine also showed a protection against renal dysfunction and tubular injury with its restoration of the increased glucose transporter 9 and renal-specific transporter in renal brush bolder membrane and the decreased organic anion transporter 1 and adenosine-triphosphate-binding cassette transporter 2 in the renal cortex in this model. These protective effects were relevant to the anti-inflammatory action by inhibiting the production of inflammatory cytokines including interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α in renal tissue of high-fructose-fed rat, being more likely to suppress renal NOD-like receptor superfamily, pyrin domain containing 3 inflammasome activation than nuclear factor κB activation. Subsequently, betaine with anti-inflammation ameliorated insulin signaling impairment by reducing the up-regulation of suppressor of cytokine signaling 3 and lipid accumulation partly by regulating peroxisome proliferator-activated receptor α/palmityltransferase 1/carnitine/organic cation transporter 2 pathway in kidney of high-fructose-fed rats. These results indicate that the inflammatory inhibition plays a pivotal role in betaine's improvement of high-fructose-induced renal injury with insulin resistance and lipid accumulation in rats., (© 2014.)

In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The aim of the present study was to investigate the effects of cortex fraxini coumarines esculetin, esculin, fraxetin and fraxin on renal dysfunction and expression abnormality of renal organic ion transporters in hyperuricemic animals. Mice were orally given 250 mg/kg oxonate for seven consecutive days to induce hyperuricemia and renal dysfunction. After 1h of oxonate induction daily, animals were orally treated with esculetin, esculin, fraxetin and fraxin at 20 and 40 mg/kg, respectively. Esculetin, esculin, fraxetin and fraxin significantly decreased serum urate, creatinine and blood urea nitrogen levels and increased urine urate and creatinine excretion in hyperuricemic mice. Esculetin and esculin up-regulated expressions of renal organic anion transporter 1 (mOAT1), organic cation and carnitine transporters (mOCT1-2 and mOCTN1-2), but failed to affect renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) in this model. Fraxetin specifically inhibited renal mURAT1, while fraxin extensively interacted with renal mGLUT9, mURAT1, mOAT1 and mOCT1 in hyperuricemic mice. Furthermore, esculetin, fraxetin and fraxin increased mABCG2 mRNA expression and decreased its protein levels in renal apical membrane in hyperuricemic mice. These results indicate that esculetin and esculin have beneficial effects on hyperuricemia and renal dysfunction, resulting in restoration of mOAT1, mOCT1-2 and mOCTN1-2, and fraxetin and fraxin enhance urate excretion partly by inhibiting mURAT1 or mGLUT9 in kidney of hyperuricemic mice. Regulation of mABCG2 by cortex fraxini coumarines may be partly contributed to their beneficial actions. This study provides an evidence to support clinical therapeutic effects of cortex fraxini coumarines on hyperuricemia with renal dysfunction., (Copyright © 2011 Elsevier B.V. All rights reserved.)