title: Ex vivo modeling of chemical synergy in prenatal kidney cystogenesis.
abstract: Cyclic adenosine monophosphate (cAMP) drives genetic polycystic kidney disease (PKD) cystogenesis. Yet within certain PKD families, striking differences in disease severity exist between affected individuals, and genomic and/or environmental modifying factors have been evoked to explain these observations. We hypothesized that PKD cystogenesis is accentuated by an aberrant fetal milieu, specifically by glucocorticoids. The extent and nature of cystogenesis was assessed in explanted wild-type mouse embryonic metanephroi, using 8-Br-cAMP as a chemical to mimic genetic PKD and the glucocorticoid dexamethasone as the environmental modulator. Cysts and glomeruli were quantified by an observer blinded to culture conditions, and tubules were phenotyped using specific markers. Dexamethasone or 8-Br-cAMP applied on their own produced cysts predominantly arising in proximal tubules and descending limbs of loops of Henle. When applied together, however, dexamethasone over a wide concentration range synergized with 8-Br-cAMP to generate a more severe, glomerulocystic, phenotype; we note that prominent glomerular cysts have been reported in autosomal dominant PKD fetal kidneys. Our data support the idea that an adverse antenatal environment exacerbates renal cystogenesis.
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and St Mary's and Manchester Children's Hospital, Manchester, United Kingdom. corina.anders@manchester.ac.uk
authors.forename: Corina
authors.initials: C
authors.lastname: Anders
authors.forename: Nick
authors.initials: N
authors.lastname: Ashton
authors.forename: Parisa
authors.initials: P
authors.lastname: Ranjzad
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dilworth
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000196:embryology* / Q000473:pathology; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology; D007668:Kidney / Q000196:embryology* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D007690:Polycystic Kidney Diseases / Q000139:chemically induced / Q000196:embryology* / Q000473:pathology; D011247:Pregnancy
chemical_list: D005938:Glucocorticoids; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003907:Dexamethasone
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