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Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the antifibrotic and renoprotective action of RAASi in a rat model of streptozotocin\u2010induced DKD.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies on proximal tubular cells and renal fibroblasts were also performed to further clarify the signal transduction pathways that are directly altered by hyperglycaemia. After 5\u00a0weeks of diabetes, male Wistar rats were treated for two more weeks\n                      <jats:italic>per os<\/jats:italic>\n                      with the RAASi ramipril, losartan, spironolactone or eplerenone. Proximal tubular cells were cultured in normal or high glucose (HG) medium and treated with RAASi. Platelet\u2010derived growth factor (PDGF) or connective tissue growth factor (CTGF\/CCN2)\u2010induced renal fibroblasts were also treated with various RAASi. In diabetic rats, reduced renal function and interstitial fibrosis were ameliorated and elevated renal profibrotic factors (TGF\u03b21, PDGF, CTGF\/CCN2, MMP2, TIMP1) and alpha\u2010smooth muscle actin (\u03b1SMA) levels were decreased by RAASi. HG increased growth factor production of HK\u20102 cells, which in turn induced activation and \u03b1SMA production of fibroblasts. RAASi decreased tubular PDGF and CTGF expression and reduced production of extracellular matrix (ECM) components in fibroblasts. In proximal tubular cells, hyperglycaemia\u2010induced growth factor production increased renal fibroblast transformation, contributing to the development of fibrosis. RAASi, even in non\u2010antihypertensive doses, decreased the production of profibrotic factors and directly prevented fibroblast activation. All these findings suggest a novel therapeutic role for RAASi in the treatment of renal fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp277002","type":"journal-article","created":{"date-parts":[[2018,10,16]],"date-time":"2018-10-16T03:30:34Z","timestamp":1539660634000},"page":"193-209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["RAAS inhibitors directly reduce diabetes\u2010induced renal fibrosis via growth factor inhibition"],"prefix":"10.1113","volume":"597","author":[{"given":"Sandor","family":"Koszegi","sequence":"first","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-2752","authenticated-orcid":false,"given":"Agnes","family":"Molnar","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"},{"name":"1st Department of Paediatrics Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilla","family":"Lenart","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Hodrea","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora Bianka","family":"Balogh","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"},{"name":"1st Department of Paediatrics Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Lakat","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Szkibinszkij","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"},{"name":"Department of Transplantation and Surgery Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Hosszu","sequence":"additional","affiliation":[{"name":"MTA\u2010SE \u201cLend\u00fclet\u201d Diabetes Research Group Hungarian Academy of Sciences and Semmelweis University  Budapest Hungary"},{"name":"1st Department of Paediatrics Semmelweis University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6979-0632","authenticated-orcid":false,"given":"Nadja","family":"Sparding","sequence":"additional","affiliation":[{"name":"Nordic Bioscience Biomarkers &amp; 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