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Published on: November 7, 2017
Cux-1 transgenic mice develop glomerulosclerosis and interstitial fibrosis
Jennifer G Brantley1, Madhulika Sharma, Neal I Alcalay
1Department of Anatomy and Cell Biology and University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
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.
Insights
Ectopic expression of the Cux-1 gene in mice causes mesangial cell proliferation and expansion, leading to early signs of glomerulonephritis and kidney damage. This study highlights Cux-1
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Genetics
Background:
- Cux-1 is a homeobox gene crucial for kidney development.
- Ectopic Cux-1 expression in mice induces renal hyperplasia and downregulates p27.
- Reduced p27 is linked to mesangial cell proliferation and glomerular disease.
Purpose of the Study:
- To investigate glomerular changes in Cux-1 transgenic mice.
- To assess the role of Cux-1 in mesangial cell proliferation and matrix deposition.
- To evaluate the impact of Cux-1 on renal function and podocyte architecture.
Main Methods:
- Morphological analysis of adult transgenic mouse kidneys.
- Immunohistochemistry to quantify glomerular cell numbers.
- Immunofluorescence and Western blotting for type IV collagen deposition.
- Assessment of renal function via serum and urine analysis.
Main Results:
- Ectopic Cux-1 expression in mesangial cells increased cell proliferation and mesangial matrix expansion.
- Increased type IV collagen deposition and podocyte foot process effacement were observed.
- Transgenic mice showed interstitial fibrosis and increased urinary albumin excretion.
Conclusions:
- Increased Cux-1 expression in mesangial cells drives proliferation and matrix expansion.
- Cux-1-induced changes disrupt podocyte architecture, impairing kidney filtration.
- Cux-1 expression is sufficient to initiate early-stage mesangioproliferative glomerulonephritis.
