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However, the molecular mechanisms of increased Nox4 expression induced by hyperglycaemia remain to be elucidated. Here, the role of the connexin32\u2013Nox4 signalling axis in diabetic nephropathy and its related mechanisms were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Diabetes was induced in mice by low\u2010dose streptozotocin (STZ) combined with a high\u2010fat diet. Effects of connexin32 on Nox4 expression and on renal function and fibrosis in STZ\u2010induced diabetic mice were investigated using adenovirus\u2010overexpressing connexin32 and connexin32\u2010deficient mice. Interactions between connexin32 and Nox4 were analysed by co\u2010immunoprecipitation and immunofluorescence assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Connexin32 was down\u2010regulated in the kidneys of STZ\u2010induced diabetic mice. Overexpression of connexin32 reduced expression of Nox4 and improved renal function and fibrosis in diabetic mice, whereas connexin32 deficiency had opposite effects. Down\u2010regulation of fibronectin expression by connexin32 was not dependent on gap junctional intercellular communication involving connexin32. Connexin32 interacted with Nox4 and reduced the generation of hydrogen peroxide, leading to the down\u2010regulation of fibronectin expression. Mechanistically, connexin32 decreased Nox4 expression by promoting its K48\u2010linked polyubiquitination. Interestingly, Smurf1 overexpression inhibited K48\u2010linked polyubiquitination of Nox4. Furthermore, connexin32 interacted with Smurf1 and inhibited its expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Connexin32 ameliorated renal fibrosis in diabetic mice by promoting K48\u2010linked Nox4 polyubiquitination and degradation via inhibition of Smurf1 expression. Targeting the connexin32\u2013Nox4 signalling axis may contribute to the development of novel treatments for diabetic nephropathy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14853","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T17:03:58Z","timestamp":1567098238000},"page":"145-160","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48\u2010linked NADPH oxidase 4 polyubiquitination and degradation"],"prefix":"10.1111","volume":"177","author":[{"given":"Zhiquan","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Pharmacology, School of Pharmacy Guangxi Medical University  Nanning China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Design and 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