Effects of Shizhifang on NLRP3 Inflammasome Activation and Renal Tubular Injury in Hyperuricemic Rats

Wu, Yansheng; He, Fangping; Li, Yingqiao; Wang, Huiling; Shi, Liqiang; Wan, Qiang; Ou, Jiaoying; Zhang, Xiaoying; Huang, Di; Lin, Xu; Peng, Lin; Yang, Guangming; He, Liqun; Gao, Jiandong

doi:10.1155/2017/7674240

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…The above studies have described that traditional Chinese medicine can reduce uric acid levels in the body by inhibiting the inflammatory state of hyperuricemia or regulating the expression of uric acid transporter or regulating XOD activity, or through a combination. The anti-inflammation effect of SZF has been reported in our previous study [ 45 ]. This article explores its effect on uric acid metabolism ulteriorly.…”

Section: Discussionsupporting

confidence: 58%

Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats

Yi-xing

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Objective To explore the effect and mechanism of ShiZhiFang on uric acid metabolism. Methods 40 rats were divided into normal group, model group, ShiZhiFang group, and benzbromarone group. The hyperuricemic rat model was induced by yeast gavage at 15 g/kg and potassium oxonate intraperitoneal injection at 600 mg/kg for two weeks. During the next two weeks, ShiZhiFang group rats were given ShiZhiFang by gavage, and benzbromarone group rats were given benzbromarone by gavage. The serum uric acid, creatinine, blood urea nitrogen, XOD activity, urinary uric acid, urinary β2-MG, and histopathological changes were observed in the rats of each group after treatment. Results The hyperuricemic model was established successfully and did not show the increase of serum creatinine and blood urea nitrogen. Compared with the model group, the serum uric acid, serum XOD activity, and urinary β2-MG were significantly decreased (p < 0.05), and 24 h urinary uric acid excretion was significantly decreased (p < 0.01) in ShiZhiFang group, whereas the two treatment groups were of no statistical significant in above indicators (p > 0.05); renal histopathology showed that the lesions in two treatment groups were reduced compared to the model groups. The gene and protein expression of uric acid anion transporters rOAT1 and rOAT3 in the kidney was significantly higher than that in model group (p < 0.01). Conclusion The model is suitable for the study of primary hyperuricemia. The mechanisms of ShiZhiFang on uric acid metabolism in hyperuricemic rats may be involved in reducing the activity of serum XOD and promoting the transcription and expression of rOAT1 and rOAT3 in the kidney.

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Section: Discussionsupporting

confidence: 58%

Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats

Yi-xing

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…In our study, the HN mice showed a significant decrease in renal function with the increased Scr, BUN, and kidney injury biomarkers (NGAL, cystatin C Kim-1, and IL-18). Moreover, we discovered that NLRP3 inflammasome activation in HN injury, and upregulation of Bax, cleaved caspase-3 and caspase-9, while downregulation of Bcl-2 were observed in the HN kidney tissues, which was consistent with previous studies (Wu et al, 2017;Wang et al, 2018;Tan et al, 2019;Zhang et al, 2019). Therefore, using a properly scientific approach to test whether a therapeutic drug could inhibit NLRP3 inflammasome activation and apoptosis in HN provided evidence-based guidance for clinical practice.…”

Section: Discussionsupporting

confidence: 88%

Scutellarin Ameliorates Renal Injury via Increasing CCN1 Expression and Suppressing NLRP3 Inflammasome Activation in Hyperuricemic Mice

Chen

et al. 2020

Front. Pharmacol.

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Considerable evidences have indicated that elevated uric acid (UA) was involved in renal tubular injury leading to hyperuricemic nephropathy (HN). Scutellarin is a biologically active flavonoid derived from the Chinese traditional herb Erigeron breviscapus Hand-Mazz, which has been widely used in the treatment of cardiovascular and cerebrovascular diseases. In the present study, we analyzed the effect of scutellarin on HN, by using C57BL/6 mice and human renal tubular epithelial cell line HK-2 which was subjected to adenine/potassium oxonate and UA to mimic a HN injury. The HN mice showed a significant decrease in renal function with the increased SCr and blood urea nitrogen (BUN) (p < 0.05). Hematoxylin-eosin staining results showed a histological injury in HN mice kidney tissues with severe tubular damage. Scutellarin dose dependently alleviated the renal injury of the HN model (p < 0.05), and a dose of 20 mg/kg/day remarkably reduced the Scr level (26.10 ± 3.23 μmol/ml vs. 48.39 ± 7.51 μmol/ml, p < 0.05) and BUN (151.12 ± 30.24 mmol/L vs. 210.43 ± 45.67 mmol/ L, p < 0.05) compared with the HN model group. Similarly, scutellarin decreased NGAL, Kim-1, cystatin C, and IL-18 protein expression levels in HN mouse (p < 0.05). Overexpressed CCN1 could not induce NLRP3 inflammasome activation, with no change of mRNA and protein expression levels of NLRP3, ASC, and pro-caspase-1 compared with the control HK-2. However, HK-2 showed a significant NLRP3 inflammasome activation and apoptosis. Importantly, knockdown of CCN1 not only aggravated NLRP3 inflammasome activation and apoptosis but also abrogated the protective effect of scutellarin in UA-induced HK-2 injury. Thus, scutellarin might alleviate HN progression via a mechanism involved in CCN1 regulation on NLRP3 inflammasome activation.

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“…As mentioned above, the release of pro-inflammatory cytokines is the key of kidney inflammation, and NLRP3 inflammatory pathway plays a crucial role in regulating inflammation ( Wu et al, 2017 ). The NLRP3 inflammasome is an intracellular multiprotein complex composed of a receptor NLRP3 (NACHT, LRR, and PYD domain-containing protein 3, cytosolic sensor protein), an adaptor ASC (an apoptosis-associated speck-like protein containing a caspase recruitment domain), and an effector caspase-1 (cysteinyl aspartate specific proteinase-1).…”

Section: Discussionmentioning

confidence: 99%

Anti-Hyperuricemic and Nephroprotective Effects of Dihydroberberine in Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice

Lin

et al. 2021

Front. Pharmacol.

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Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro, DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.

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Effects of Shizhifang on NLRP3 Inflammasome Activation and Renal Tubular Injury in Hyperuricemic Rats

Cited by 12 publications

References 36 publications

Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats

Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats

Scutellarin Ameliorates Renal Injury via Increasing CCN1 Expression and Suppressing NLRP3 Inflammasome Activation in Hyperuricemic Mice

Anti-Hyperuricemic and Nephroprotective Effects of Dihydroberberine in Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice

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