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Six2cre -mediated deletion of Frs2α ( Six2creFrs2αKO ), a major fibroblast growth factor receptor (Fgfr) docking protein in mouse nephron progenitors results in perinatal renal hypoplasia; however, postnatal  Six2creFrs2αKO  kidneys develop cysts. We sought to determine the pathogenesis of  Six2creFrs2αKO  cyst formation. We performed histological assays, Western blots, and quantitative PCR (qPCR). While embryonic day (E) 18.5  Six2Frs2αKO  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.  Six2creFrs2αKO  kidneys also had upregulation of Wnt/βcatenin 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  Gli1  (hedgehog readout) in postnatal  Six2creFrs2αKO  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 “AKI” pathways may drive pathogenesis in PKD.

Six2creFrs2α knockout mice are a novel model of renal cystogenesis