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Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1\u03b1 upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1\u03b1 resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1\u03b1 prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1\u03b1 in human primary tubular cells. Next to HIF-1\u03b1 and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1\u03b1- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1\u03b1 and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1\u03b1- and cAMP-dependent in vitro cyst enlargement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\u2022 MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model.<\/jats:p>\n                    <jats:p>\u2022 MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1\u03b1.<\/jats:p>\n                    <jats:p>\u2022 ABCA1, transport protein for MIF, is also regulated by HIF-1\u03b1 in vitro and in vivo.<\/jats:p>\n                    <jats:p>\u2022 MIF is additionally regulated by cAMP, a strong promotor of cyst growth.<\/jats:p>\n                    <jats:p>\u2022 MIF-inhibitor ISO-1 reduces HIF-1\u03b1- and cAMP-dependent cyst growth.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-020-01964-1","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T19:05:47Z","timestamp":1599159947000},"page":"1547-1559","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Macrophage migration inhibitory factor is regulated by HIF-1\u03b1 and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner"],"prefix":"10.1007","volume":"98","author":[{"given":"Wajima","family":"Safi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Grampp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Sch\u00f6del","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3730-5425","authenticated-orcid":false,"given":"Bjoern","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,4]]},"reference":[{"key":"1964_CR1","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1172\/JCI72272","volume":"124","author":"PC Harris","year":"2014","unstructured":"Harris PC, Torres VE (2014) Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. 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