Cux-1 transgenic mice develop glomerulosclerosis and interstitial fibrosis

Kidney Int. 2003 Apr;63(4):1240-8. doi: 10.1046/j.1523-1755.2003.00889.x.

Abstract

Background: Cux-1 is a murine homeobox gene that is highly expressed in the nephrogenic zone of the developing kidney. Transgenic mice ectopically expressing Cux-1 develop renal hyperplasia associated with down-regulation of the cyclin kinase inhibitor p27. Because the reduction of p27 has been associated with mesangial cell proliferation and glomerular disease, we evaluated glomerular changes in Cux-1 transgenic mice.

Methods: Adult kidneys from Cux-1 transgenic mice were analyzed morphologically for changes in glomerular cell number and for changes in mesangial and interstitial extracellular matrix deposition. Mesangial matrix expansion was identified by light microscopy. Glomerular cell number was performed following immunohistochemistry. Type IV collagen deposition was analyzed by immunofluoresence and Western blotting. Renal function was evaluated by serum protein, blood urea nitrogen (BUN), creatinine, and electrolyte analysis, and by urine protein and creatinine analysis.

Results: In adult transgenic glomeruli, Cux-1 was ectopically expressed in mesangial cells, and this was associated with an increase in mesangial cell number, resulting from an increase in proliferation. There was a marked increase in mesangial matrix area in transgenic mice compared to non-transgenic littermates, related to an increase in type IV collagen. Podocyte foot process effacement was observed in transgenic mice, and this was related to an increase in urinary albumin. Interstitial fibrosis was also observed in transgenic kidneys.

Conclusion: These observations indicate that increased expression of Cux-1 in mesangial cells results in cell proliferation and mesangial expansion. In addition, these changes are potentially related to disruption of podocyte architecture leading to loss of filtration. These results suggest that expression of Cux-1 is sufficient to induce the early events of mesangioproliferative glomerulonephritis.

MeSH terms

  • Animals
  • Cell Division
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Glomerulonephritis, Membranoproliferative / genetics
  • Glomerulonephritis, Membranoproliferative / pathology
  • Glomerulonephritis, Membranoproliferative / physiopathology
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Glomerulosclerosis, Focal Segmental / physiopathology*
  • Homeodomain Proteins
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics*
  • Proteinuria / genetics
  • Proteinuria / pathology
  • Proteinuria / physiopathology
  • Repressor Proteins / genetics*

Substances

  • Cux1 protein, mouse
  • Homeodomain Proteins
  • Nuclear Proteins
  • Repressor Proteins