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      Febuxostat Attenuates Renal Damage besides Exerting Hypouricemic Effect in Streptozotocin-Induced Diabetic Rats

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          Abstract

          Aim. In this study, we aimed to investigate the effects of febuxostat, a novel inhibitor of xanthine oxidase (XO), on renal damage in streptozotocin- (STZ-) induced diabetic rats. Methods. Diabetes was induced by the intraperitoneal injection of STZ in male Sprague-Dawley rats. Sham-injected rats served as controls. The control and diabetic rats were treated with and without febuxostat for 8 weeks, respectively. Fasting blood and 24-h urine samples were collected every 4 weeks. Rat livers were extracted for detecting gene expression, content, and bioactivity of XO. Results. Diabetic rats showed significantly increased serum uric acid (SUA), serum creatinine (SCr), and urea nitrogen (BUN) levels. Daily urinary albumin (UAE), uric acid (UUA), and creatinine (UCr) excretion were also significantly increased in these rats. In diabetic rats, at week 8, febuxostat decreased SUA by 18.9%, while UAA was increased by 52.0%. However, UCr and urinary urea nitrogen (UUN) levels remained unchanged, while SCr and BUN levels decreased by >30% in these rats. Although hepatic gene expression, content, and activity of XO increased significantly in diabetic rats, febuxostat only slightly decreased its content. Conclusions. Febuxostat significantly attenuated renal damage in STZ-induced diabetic rats in addition to exerting hypouricemic effect.

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          Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.

          Dalila Corry, Pirooz Eslami, Kei Yamamoto … (2008)
          Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however. We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS). Rat VSMC were exposed to 0-300 micromol uric acid for 48 h. Uric acid (200 and 300 micromol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10(-6) mol losartan or by 10(-6) mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril. These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.
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            Soluble Uric Acid Activates the NLRP3 Inflammasome

            Tarcio Braga, Maria Fernanda Forni, Matheus Correa-Costa … (2017)
            Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3 −/− macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88 −/− cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.
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              Quercetin and Allopurinol Ameliorate Kidney Injury in STZ-Treated Rats with Regulation of Renal NLRP3 Inflammasome Activation and Lipid Accumulation

              Chuang Wang, Ying Pan, Qing-Yu Zhang … (2012)
              Hyperuricemia, hyperlipidemia and inflammation are associated with diabetic nephropathy. The NLRP3 inflammasome-mediated inflammation is recently recognized in the development of kidney injury. Urate and lipid are considered as danger signals in the NLRP3 inflammasome activation. Although dietary flavonoid quercetin and allopurinol alleviate hyperuricemia, dyslipidmia and inflammation, their nephroprotective effects are currently unknown. In this study, we used streptozotocin (STZ)-induced diabetic nephropathy model with hyperuricemia and dyslipidemia in rats, and found over-expression of renal inflammasome components NLRP3, apoptosis-associated speck-like protein and Caspase-1, resulting in elevation of IL-1β and IL-18, with subsequently deteriorated renal injury. These findings demonstrated the possible association between renal NLRP3 inflammasome activation and lipid accumulation to superimpose causes of nephrotoxicity in STZ-treated rats. The treatment of quercetin and allopurinol regulated renal urate transport-related proteins to reduce hyperuricemia, and lipid metabolism-related genes to alleviate kidney lipid accumulation in STZ-treated rats. Furthermore, quercetin and allopurinol were found to suppress renal NLRP3 inflammasome activation, at least partly, via their anti-hyperuricemic and anti-dyslipidemic effects, resulting in the amelioration of STZ-induced the superimposed nephrotoxicity in rats. These results may provide a basis for the prevention of diabetes-associated nephrotoxicity with urate-lowering agents such as quercetin and allopurinol.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nephrol
                Journal ID (iso-abbrev): Int J Nephrol
                Journal ID (publisher-id): IJN
                Title: International Journal of Nephrology
                Publisher: Hindawi
                ISSN (Print): 2090-214X
                ISSN (Electronic): 2090-2158
                Publication date (Print): 2017
                Publication date (Electronic): 19 April 2017
                Volume: 2017
                Electronic Location Identifier: 2739539
                Affiliations
                1Department of Endocrinology, Guangzhou Red Cross Hospital, Medical School of Jinan University, No. 396 Tong Fu Zhong Road, Guangzhou, China
                2Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital, Medical School of Jinan University, No. 396 Tong Fu Zhong Road, Guangzhou, China
                3Department of Nephrology, Guangzhou Red Cross Hospital, Medical School of Jinan University, No. 396 Tong Fu Zhong Road, Guangzhou, China
                4Southern Medical University, No. 1023-1063 Southern Sha Tai Road, Guangzhou, China
                Author notes
                *Jianmin Ran: ranjm@ 123456msn.com

                Academic Editor: Franca Anglani

                Author information
                http://orcid.org/0000-0003-1364-9469
                Article
                DOI: 10.1155/2017/2739539
                PMC ID: 5414495
                SO-VID: df414352-1f66-4e24-844c-42704e694088
                Copyright © Copyright © 2017 Jianmin Ran et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 3 March 2017
                Date revision received : 20 March 2017
                Date accepted : 27 March 2017
                Funding
                Funded by: Guangzhou Science and Technology Project Fund
                Award ID: 201300000181
                Award ID: 2014Y2-00145
                Award ID: 2014Y2-00166
                Award ID: 14A33151295
                Award ID: 2014J4100076
                Funded by: Guangzhou Scientific Fund for Clinical Study and Translational Medicine
                Award ID: 2014Y2-00549
                Funded by: Guangdong Science and Technology Project Fund for Key Scientific Research Base
                Award ID: 2014B030303002
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Nephrology
                Data availability:
                ScienceOpen disciplines: Nephrology

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