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Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>C57BL\/6 mice were treated with angiotensin II by subcutaneous infusion for 1\u00a0month to develop nephropathy. Mice were treated with either adeno\u2010associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I\u2010201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I\u2010201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll\u2010like receptor 4 (TLR4) and JAK2, which was independent of IL\u20106\/gp130 and angiotensin AT<jats:sub>1<\/jats:sub> receptors. Angiotensin II\u2010mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I\u2010201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14686","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T18:03:58Z","timestamp":1554746638000},"page":"2627-2641","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inhibition of STAT3 activation mediated by toll\u2010like receptor 4 attenuates angiotensin II\u2010induced renal fibrosis and 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