Inducible gene modification using the Cre/loxP system provides a valuable tool for analysis of gene function in specific tissues of live animals. To investigate the therapeutic role of kallikreins (klk) against spontaneous lupus nephritis, we created a transgenic mouse model, KSP-CreERT2/CAG-LacZ(flox)-mKlk1-GFP/Sle1Sle3. This model is based on the expression of a tamoxifen-inducible Cre recombinase under the control of kidney specific promoter (KSP), and its activation will cause the deletion of loxP-flanked LacZ gene and turned on the mKlk1 expression under the control of CAG promoter. In the transgenic mice, the expression of CreERT2 was restricted to KSP+ kidney tubular cells. The transgenic mice were injected with either tamoxifen or vehicle (controls) at 3-mo age and followed up for 6 months for the klk expression and nephritis phenotype. The elevated expression of mKlk1 in the kidney and urine was detected in tamoxifen induced mice but not in controls. At 9-mo age, more than 80% of vehicle injected mice developed severe lupus nephritis as evidenced with increased level of serum BUN (72 ±23mg/dL), proteinuria (21±7mg/24hr) and renal pathology. However, the tamoxifen injected mice showed significantly reduced level of serum BUN(17±8mg/dL), proteinuria (7±3mg/24hr) and mild or no renal pathology change (p<0.05). Tamoxifen induced upregulation of mKlk1 in mouse kidney increased the NO production and suppressed the apoptosis of kidney tubular cells in B6.Sle1.Sle3 mice.
- Copyright © 2011 by The American Association of Immunologists, Inc.