Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction

Sepideh Sheybani-Deloui, Lijun Chi, Marian V. Staite, Jason E. Cain, Brian J. Nieman, R. Mark Henkelman, Brandon J. Wainwright, S. Steven Potter, Darius J. Bagli, Armando J. Lorenzo, Norman D. Rosenblum

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Abstract

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

Original languageEnglish
Pages (from-to)532-544
Number of pages13
JournalJournal of the American Society of Nephrology
Volume29
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018
Externally publishedYes

Cite this

Sheybani-Deloui, S., Chi, L., Staite, M. V., Cain, J. E., Nieman, B. J., Mark Henkelman, R., ... Rosenblum, N. D. (2018). Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction. Journal of the American Society of Nephrology, 29(2), 532-544. https://doi.org/10.1681/ASN.2017050482
Sheybani-Deloui, Sepideh ; Chi, Lijun ; Staite, Marian V. ; Cain, Jason E. ; Nieman, Brian J. ; Mark Henkelman, R. ; Wainwright, Brandon J. ; Steven Potter, S. ; Bagli, Darius J. ; Lorenzo, Armando J. ; Rosenblum, Norman D. / Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 2. pp. 532-544.
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title = "Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction",
abstract = "Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.",
author = "Sepideh Sheybani-Deloui and Lijun Chi and Staite, {Marian V.} and Cain, {Jason E.} and Nieman, {Brian J.} and {Mark Henkelman}, R. and Wainwright, {Brandon J.} and {Steven Potter}, S. and Bagli, {Darius J.} and Lorenzo, {Armando J.} and Rosenblum, {Norman D.}",
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Sheybani-Deloui, S, Chi, L, Staite, MV, Cain, JE, Nieman, BJ, Mark Henkelman, R, Wainwright, BJ, Steven Potter, S, Bagli, DJ, Lorenzo, AJ & Rosenblum, ND 2018, 'Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction', Journal of the American Society of Nephrology, vol. 29, no. 2, pp. 532-544. https://doi.org/10.1681/ASN.2017050482

Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction. / Sheybani-Deloui, Sepideh; Chi, Lijun; Staite, Marian V.; Cain, Jason E.; Nieman, Brian J.; Mark Henkelman, R.; Wainwright, Brandon J.; Steven Potter, S.; Bagli, Darius J.; Lorenzo, Armando J.; Rosenblum, Norman D.

In: Journal of the American Society of Nephrology, Vol. 29, No. 2, 01.02.2018, p. 532-544.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction

AU - Sheybani-Deloui, Sepideh

AU - Chi, Lijun

AU - Staite, Marian V.

AU - Cain, Jason E.

AU - Nieman, Brian J.

AU - Mark Henkelman, R.

AU - Wainwright, Brandon J.

AU - Steven Potter, S.

AU - Bagli, Darius J.

AU - Lorenzo, Armando J.

AU - Rosenblum, Norman D.

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N2 - Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

AB - Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm-derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm-derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

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