Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

J Clin Invest. 2004 Apr;113(7):1051-8. doi: 10.1172/JCI20049.

Abstract

Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality, in causing congenital obstructive nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Humans
  • Integrases / genetics
  • Integrases / metabolism
  • Mesoderm / metabolism*
  • Mice
  • Mice, Transgenic
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Transcription Factors*
  • Ureter / abnormalities
  • Ureter / embryology*
  • Ureter / metabolism
  • Urinary Tract / abnormalities
  • Urinary Tract / embryology*
  • Urinary Tract / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • Paired Box Transcription Factors
  • Transcription Factors
  • Viral Proteins
  • Pax3 protein, mouse
  • Cre recombinase
  • Integrases
  • Calcineurin