WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling
Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel...
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| description | Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN. |
| doi_str_mv | 10.1155/2020/7950457 |
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Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2020/7950457</identifier><identifier>PMID: 32566101</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Aldehyde Reductase - antagonists & inhibitors ; Aldehyde Reductase - metabolism ; Aldose reductase ; Animals ; Bone morphogenetic proteins ; Cells, Cultured ; Creatinine ; Cytokines ; Dextrose ; Diabetes ; Diabetic nephropathies ; Diabetic Nephropathies - drug therapy ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - physiopathology ; Diabetic nephropathy ; Drug therapy ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Experiments ; Fasting ; Fibrosis ; Glucose ; Glucose - toxicity ; Inflammation - pathology ; Kidney - drug effects ; Kidney - pathology ; Kidney - physiopathology ; Kidney diseases ; Laboratory animals ; Male ; Mesangial Cells - drug effects ; Mesangial Cells - metabolism ; Mesangial Cells - pathology ; Microscopy ; Models, Biological ; NF-E2-Related Factor 2 - metabolism ; Oxidative stress ; Oxidative Stress - drug effects ; Polyols ; Rats, Sprague-Dawley ; Reactive oxygen species ; Signal Transduction ; Smad Proteins - metabolism ; Streptozocin ; Transforming Growth Factor beta1 - metabolism</subject><ispartof>Oxidative medicine and cellular longevity, 2020, Vol.2020 (2020), p.1-21</ispartof><rights>Copyright © 2020 Xiaoyu Zhou et al.</rights><rights>COPYRIGHT 2020 John Wiley & Sons, Inc.</rights><rights>Copyright © 2020 Xiaoyu Zhou et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. http://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2020 Xiaoyu Zhou et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-13cddbe8be7e734e134440d3e783e2c02ce7d8af32d5368b96d0aa17c911f1013</citedby><cites>FETCH-LOGICAL-c499t-13cddbe8be7e734e134440d3e783e2c02ce7d8af32d5368b96d0aa17c911f1013</cites><orcidid>0000-0002-4251-8874 ; 0000-0002-2098-9907 ; 0000-0002-6911-5784 ; 0000-0002-7085-7259 ; 0000-0002-5907-3875</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277034/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277034/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,4023,27922,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32566101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gambini, Juan</contributor><contributor>Juan Gambini</contributor><creatorcontrib>He, Zhonggui</creatorcontrib><creatorcontrib>Wang, Shaojie</creatorcontrib><creatorcontrib>Chi, Tian-Yan</creatorcontrib><creatorcontrib>Ji, Xue-Fei</creatorcontrib><creatorcontrib>Liu, Peng</creatorcontrib><creatorcontrib>Wang, Huimin</creatorcontrib><creatorcontrib>Ying, Ke</creatorcontrib><creatorcontrib>Liu, Zheng</creatorcontrib><creatorcontrib>Zhou, Xiaoyu</creatorcontrib><creatorcontrib>Zou, Li-Bo</creatorcontrib><title>WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.</description><subject>Aldehyde Reductase - antagonists & inhibitors</subject><subject>Aldehyde Reductase - metabolism</subject><subject>Aldose reductase</subject><subject>Animals</subject><subject>Bone morphogenetic proteins</subject><subject>Cells, Cultured</subject><subject>Creatinine</subject><subject>Cytokines</subject><subject>Dextrose</subject><subject>Diabetes</subject><subject>Diabetic nephropathies</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Diabetic Nephropathies - physiopathology</subject><subject>Diabetic nephropathy</subject><subject>Drug therapy</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Experiments</subject><subject>Fasting</subject><subject>Fibrosis</subject><subject>Glucose</subject><subject>Glucose - toxicity</subject><subject>Inflammation - pathology</subject><subject>Kidney - drug effects</subject><subject>Kidney - pathology</subject><subject>Kidney - physiopathology</subject><subject>Kidney diseases</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Mesangial Cells - drug effects</subject><subject>Mesangial Cells - metabolism</subject><subject>Mesangial Cells - pathology</subject><subject>Microscopy</subject><subject>Models, Biological</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Polyols</subject><subject>Rats, Sprague-Dawley</subject><subject>Reactive oxygen species</subject><subject>Signal Transduction</subject><subject>Smad Proteins - metabolism</subject><subject>Streptozocin</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkU1v1DAQhiMEoqVw44wscWRDxx-J4wtSVKAtWhWJD3G0HGeycZWNF9tbtP8eV7ts4cbJY83jRzN-i-IlhbeUVtU5AwbnUlUgKvmoOKVKsBKUEo-PNcBJ8SzGW4CaM0GfFiecVXVNgZ4W6cenkqsFMTNpp95HJF-w39pkcnU9j65zyYcFadc4OR9MwpiB2UxkidH5ORI3k_fOdJicJTe4GYPfmDTuSLcjrU3uziQ3r8hNGBj56lb5Zb4-L54MZor44nCeFd8_fvh2cVUuP19eX7TL0gqlUkm57fsOmw4lSi6QciEE9Bxlw5FZYBZl35iBs77iddOpugdjqLSK0iFvx8-Kd3vvZtutsbc4p2AmvQlubcJOe-P0v53ZjXrl77RkUgIXWfD6IAj-5xZj0rd-G_ISUeePBGgUVfBArcyE2s2DzzK7dtHqtuZV1QClMlOLPWWDjzHgcJyDgr5PUt8nqQ9JZvzV37Mf4T_RZeDNHhjd3Jtf7j91mBkczAPNoBIN8N8KJK68</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>He, Zhonggui</creator><creator>Wang, Shaojie</creator><creator>Chi, Tian-Yan</creator><creator>Ji, Xue-Fei</creator><creator>Liu, Peng</creator><creator>Wang, Huimin</creator><creator>Ying, Ke</creator><creator>Liu, Zheng</creator><creator>Zhou, Xiaoyu</creator><creator>Zou, Li-Bo</creator><general>Hindawi Publishing Corporation</general><general>Hindawi</general><general>John Wiley & Sons, Inc</general><general>Hindawi Limited</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4251-8874</orcidid><orcidid>https://orcid.org/0000-0002-2098-9907</orcidid><orcidid>https://orcid.org/0000-0002-6911-5784</orcidid><orcidid>https://orcid.org/0000-0002-7085-7259</orcidid><orcidid>https://orcid.org/0000-0002-5907-3875</orcidid></search><sort><creationdate>2020</creationdate><title>WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling</title><author>He, Zhonggui ; Wang, Shaojie ; Chi, Tian-Yan ; Ji, Xue-Fei ; Liu, Peng ; Wang, Huimin ; Ying, Ke ; Liu, Zheng ; Zhou, Xiaoyu ; Zou, Li-Bo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-13cddbe8be7e734e134440d3e783e2c02ce7d8af32d5368b96d0aa17c911f1013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aldehyde Reductase - 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Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Publishing Corporation</pub><pmid>32566101</pmid><doi>10.1155/2020/7950457</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0002-4251-8874</orcidid><orcidid>https://orcid.org/0000-0002-2098-9907</orcidid><orcidid>https://orcid.org/0000-0002-6911-5784</orcidid><orcidid>https://orcid.org/0000-0002-7085-7259</orcidid><orcidid>https://orcid.org/0000-0002-5907-3875</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Oxidative medicine and cellular longevity, 2020, Vol.2020 (2020), p.1-21 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7277034 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Wiley-Blackwell Open Access Titles; PubMed Central; Alma/SFX Local Collection |
| subjects | Aldehyde Reductase - antagonists & inhibitors Aldehyde Reductase - metabolism Aldose reductase Animals Bone morphogenetic proteins Cells, Cultured Creatinine Cytokines Dextrose Diabetes Diabetic nephropathies Diabetic Nephropathies - drug therapy Diabetic Nephropathies - metabolism Diabetic Nephropathies - physiopathology Diabetic nephropathy Drug therapy Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Experiments Fasting Fibrosis Glucose Glucose - toxicity Inflammation - pathology Kidney - drug effects Kidney - pathology Kidney - physiopathology Kidney diseases Laboratory animals Male Mesangial Cells - drug effects Mesangial Cells - metabolism Mesangial Cells - pathology Microscopy Models, Biological NF-E2-Related Factor 2 - metabolism Oxidative stress Oxidative Stress - drug effects Polyols Rats, Sprague-Dawley Reactive oxygen species Signal Transduction Smad Proteins - metabolism Streptozocin Transforming Growth Factor beta1 - metabolism |
| title | WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T21%3A43%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=WJ-39,%20an%20Aldose%20Reductase%20Inhibitor,%20Ameliorates%20Renal%20Lesions%20in%20Diabetic%20Nephropathy%20by%20Activating%20Nrf2%20Signaling&rft.jtitle=Oxidative%20medicine%20and%20cellular%20longevity&rft.au=He,%20Zhonggui&rft.date=2020&rft.volume=2020&rft.issue=2020&rft.spage=1&rft.epage=21&rft.pages=1-21&rft.issn=1942-0900&rft.eissn=1942-0994&rft_id=info:doi/10.1155/2020/7950457&rft_dat=%3Cgale_pubme%3EA635580117%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2410089190&rft_id=info:pmid/32566101&rft_galeid=A635580117&rfr_iscdi=true |