Ectopic Phosphorylated Creb Marks Dedifferentiated Proximal Tubules in Cystic Kidney Disease
| Autor: | Mary E. Taglienti, Bradley K. Yoder, Jordan A. Kreidberg, Caitlin Schaefer, Carlton M. Bates, Pawan Puri, Daniel Bushnell |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Nephron Biology CREB Article Pathology and Forensic Medicine Kidney Tubules Proximal Mice 03 medical and health sciences Cystic kidney disease medicine Polycystic kidney disease Animals Phosphorylation Cyclic AMP Response Element-Binding Protein Mice Knockout Cystic kidney Kidney Acute kidney injury Cell Dedifferentiation Kidney Diseases Cystic medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure Ureteric bud biology.protein |
| Zdroj: | The American Journal of Pathology. 188:84-94 |
| ISSN: | 0002-9440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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