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Ectopic Phosphorylated Creb Marks Dedifferentiated Proximal Tubules in Cystic Kidney Disease.

Authors
  • Puri, Pawan1
  • Schaefer, Caitlin M2
  • Bushnell, Daniel2
  • Taglienti, Mary E3
  • Kreidberg, Jordan A3
  • Yoder, Bradley K4
  • Bates, Carlton M5
  • 1 Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: [email protected]
  • 2 Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • 3 Department of Urology, Boston Children's Hospital, Boston, Massachusetts; Department of Surgery, Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Pediatrics, Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 5 Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Nephrology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Jan 01, 2018
Volume
188
Issue
1
Pages
84–94
Identifiers
DOI: 10.1016/j.ajpath.2017.09.015
PMID: 29107072
Source
Medline
License
Unknown

Abstract

Ectopic cAMP signaling is pathologic in polycystic kidney disease; however, its spatiotemporal actions are unclear. We characterized the expression of phosphorylated Creb (p-Creb), a target and mediator of cAMP signaling, in developing and cystic kidney models. We also examined tubule-specific effects of cAMP analogs in cystogenesis in embryonic kidney explants. In wild-type mice, p-Creb marked nephron progenitors (NP), early epithelial NP derivatives, ureteric bud, and cortical stroma; p-Creb was present in differentiated thick ascending limb of Henle, collecting duct, and stroma; however, it disappeared in mature NP-derived proximal tubules. In Six2cre;Frs2αFl/Fl mice, a renal cystic model, ectopic p-Creb stained proximal tubule-derived cystic segments that lost the differentiation marker lotus tetragonolobus lectin. Furthermore, lotus tetragonolobus lectin-negative/p-Creb-positive cyst segments (re)-expressed Ncam1, Pax2, and Sox9 markers of immature nephron structures and dedifferentiated proximal tubules after acute kidney injury. These dedifferentiation markers were co-expressed with p-Creb in renal cysts in Itf88 knockout mice subjected to ischemia and Six2cre;Pkd1Fl/Fl mice, other renal cystogenesis models. 8-Br-cAMP addition to wild-type embryonic kidney explants induced proximal tubular cystogenesis and p-Creb expression; these effects were blocked by co-addition of protein kinase A inhibitor. Thus p-Creb/cAMP signaling is appropriate in NP and early nephron derivatives, but disappears in mature proximal tubules. Moreover, ectopic p-Creb expression/cAMP signaling marks dedifferentiated proximal tubular cystic segments. Furthermore, proximal tubules are predisposed to become cystic after cAMP stimulation.

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