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

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.

• Authors: Pawan Puri, Caitlin M Schaefer, Daniel Bushnell, Mary E Taglienti, Jordan A Kreidberg, Bradley K Yoder, Carlton M Bates
• Journal: The American journal of pathology (Am J Pathol) Vol. 188 Issue 1 Pg. 84-94 (01 2018) ISSN: 1525-2191 [Electronic] United States
• PMID: 29107072 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cyclic AMP Response Element-Binding Protein

Topics

• Animals
• Cell Dedifferentiation (physiology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Kidney Diseases, Cystic (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism, pathology)
• Mice
• Mice, Knockout
• Phosphorylation