Cell type specific changes in BMP-7 expression contribute to the progression of kidney disease in patients with obstructive uropathy

J Urol. 2015 May;193(5 Suppl):1860-1869. doi: 10.1016/j.juro.2014.10.117. Epub 2015 Mar 24.

Abstract

Purpose: Congenital urinary tract obstruction is a leading cause of renal maldevelopment and pediatric kidney disease. Nonetheless, few groups have examined its molecular pathogenesis in humans. We evaluated the role of BMP-7, a protein required for renal injury repair and nephrogenesis, in disease progression in patients with obstructive uropathy.

Materials and methods: Whole kidney and cell specific BMP-7 expression was examined in a murine model of unilateral ureteral obstruction and in patients with congenital ureteropelvic junction obstruction. Findings were correlated with molecular markers of renal injury and clinical parameters.

Results: Unilateral ureteral obstruction led to a dramatic decrease in BMP-7 expression in the proximal and distal tubules before the onset of significant loss of renal architecture and fibrosis, suggesting that this is a critical molecular event that drives early stage disease progression. Loss of BMP-7 expression then extended to the collecting ducts and glomeruli in end stage kidney disease. When translating these findings to patients with ureteropelvic junction obstruction, global loss of BMP-7 expression correlated with a decreased number of nephrons, loss of renal architecture, severe renal fibrosis and loss of kidney function.

Conclusions: Given that BMP-7 has a critical role in renal injury repair and nephrogenesis, these findings show that cell specific changes in BMP-7 expression contribute to the onset of irreversible renal injury and impaired kidney development secondary to congenital urinary tract obstruction. Accordingly therapies that target these cell populations to restore BMP-7 activity may limit disease progression in patients with obstructive uropathy.

Keywords: bone morphogenetic protein 7; fibrosis; growth and development; kidney; ureteral obstruction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Bone Morphogenetic Protein 7 / metabolism*
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Kidney Diseases / metabolism*
  • Kidney Tubules, Distal / cytology
  • Kidney Tubules, Distal / metabolism*
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • Mice, Inbred C57BL
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Bone Morphogenetic Protein 7
  • CD68 protein, mouse
  • bmp7 protein, mouse
  • Caspase 3