Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction

J Am Soc Nephrol. 2018 Feb;29(2):532-544. doi: 10.1681/ASN.2017050482. Epub 2017 Nov 6.

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.

Keywords: kidney development; nephropathy; obstructive; pediatrics; signaling; transgenic mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Oxidoreductases / genetics
  • Animals
  • Cell Lineage
  • Child
  • Female
  • Forkhead Transcription Factors / genetics
  • Gene Expression
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Hydronephrosis / congenital
  • Hydronephrosis / genetics*
  • Hydronephrosis / pathology
  • In Situ Hybridization
  • Kidney Pelvis / embryology
  • Kidney Pelvis / metabolism
  • Male
  • Mesoderm / embryology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Patched-1 Receptor / genetics*
  • Patched-2 Receptor / genetics*
  • Signal Transduction*
  • Stem Cells / metabolism
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Transcriptome
  • Up-Regulation
  • Ureter / embryology
  • Ureter / metabolism
  • Ureteral Obstruction / congenital
  • Ureteral Obstruction / genetics*
  • Ureteral Obstruction / pathology
  • Zinc Finger Protein Gli3 / genetics*
  • Zinc Finger Protein Gli3 / metabolism

Substances

  • FOXD1 protein, human
  • Forkhead Transcription Factors
  • Foxd1 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Nerve Tissue Proteins
  • Osr1 protein, mouse
  • PTCH2 protein, human
  • Patched-1 Receptor
  • Patched-2 Receptor
  • Ptch1 protein, mouse
  • Ptch2 protein, mouse
  • Sall1 protein, mouse
  • Transcription Factors
  • Zinc Finger Protein Gli3
  • Aldehyde Oxidoreductases
  • RALDH2 protein, mouse

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