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We sought to determine the pathogenesis of <jats:italic>Six2creFrs2\u03b1KO<\/jats:italic> cyst formation. We performed histological assays, Western blots, and quantitative PCR (qPCR). While embryonic day (E) 18.5 <jats:italic>Six2Frs2\u03b1KO<\/jats:italic> kidneys were hypoplastic and not cystic, postnatal day (P) 7 mutants had proximal tubular-derived cysts that nearly replaced the renal parenchyma by P21. Mutants had high proximal tubular proliferation rates and interstitial fibrosis, similar to known polycystic kidney disease (PKD) models. <jats:italic>Six2creFrs2\u03b1KO<\/jats:italic> kidneys also had upregulation of Wnt\/\u03b2catenin signaling, macrophage infiltration and chemokine production (e.g. ectopic Ccl2 in non-dilated proximal tubules), and augmented hedgehog signaling, features also seen in other PKD models. We saw increased <jats:italic>Gli1<\/jats:italic> (hedgehog readout) in postnatal <jats:italic>Six2creFrs2\u03b1KO<\/jats:italic> interstitium and ectopic sonic hedgehog (Shh) in subsets of non-dilated P7 mutant proximal tubules (likely driving the stromal Gli expression). As ectopic tubular Shh and Ccl2 expression is seen after acute kidney injury (AKI), we interrogated another bone fide AKI marker, Kim1 and noted ectopic expression in P7 non-dilated proximal tubules. These observations suggest that aberrantly activated \u201cAKI\u201d pathways may drive pathogenesis in PKD.<\/jats:p>","DOI":"10.1038\/srep36736","type":"journal-article","created":{"date-parts":[[2016,11,17]],"date-time":"2016-11-17T12:55:09Z","timestamp":1479387309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Six2creFrs2\u03b1 knockout mice are a novel model of renal cystogenesis"],"prefix":"10.1038","volume":"6","author":[{"given":"Pawan","family":"Puri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bushnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin M.","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlton M.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,17]]},"reference":[{"key":"BFsrep36736_CR1","doi-asserted-by":"publisher","first-page":"8578","DOI":"10.1073\/pnas.161259898","volume":"98","author":"YR Hadari","year":"2001","unstructured":"Hadari, Y. 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