Six2creFrs2α knockout mice are a novel model of renal cystogenesis

Pawan Puri,Caitlin M Schaefer,Daniel Bushnell,Carlton M Bates

doi:10.1038/srep36736

Pawan Puri, Caitlin M Schaefer + Show 2 more

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https://doi.org/10.1038/srep36736

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Abstract

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.

Highlights

Six2cre-mediated deletion of factor receptor substrate 2α (Frs2α) (Six2creFrs2αKO), a major fibroblast growth factor receptor (Fgfr) docking protein in mouse nephron progenitors results in perinatal renal hypoplasia; postnatal Six2creFrs2αKO kidneys develop cysts
We examined whether Six2creFrs2αKO kidneys had increased expression of inflammatory cytokines, those that recruit monocytes/macrophages (e.g. Ccl2) or that are secreted by activated macrophages (e.g. Tnfαand Cxcl2), as in other polycystic cystic kidney disease (PKD) models[28,29,30,33,40,42]
We found that kidneys lacking Frs2α in nephron progenitors develop rapid cyst growth after birth

Summary

Introduction

Six2cre-mediated deletion of Frs2α (Six2creFrs2αKO), a major fibroblast growth factor receptor (Fgfr) docking protein in mouse nephron progenitors results in perinatal renal hypoplasia; postnatal Six2creFrs2αKO kidneys develop cysts. As ectopic tubular Shh and Ccl[2] expression is seen after acute kidney injury (AKI), we interrogated another bone fide AKI marker, Kim[1] and noted ectopic expression in P7 non-dilated proximal tubules These observations suggest that aberrantly activated “AKI” pathways may drive pathogenesis in PKD. Animal models of polycystic cystic kidney disease (PKD), causative mutations have often been identified in genes encoding for proteins that associate with primary cilia and/or that are critical for ciliary assembly and/or intraflagellar transport[14,15,16,17,18,19]. Chemokines, such as Ccl[2] (major chemotactic factor for macrophages) and Tnfα(secreted by activated macrophages) have been detected in PKD models and appear to have causative roles[28,33,34]

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