Systemic Lupus Erythematosus
Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis
Version of Record online: 25 FEB 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 3, pages 780–791, March 2013
How to Cite
Shao, X., Yang, R., Yan, M., Li, Y., Du, Y., Raman, I., Zhang, B., Wakeland, W., Igarashi, P., Mohan, C. and Li, Q.-Z. (2013), Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis. Arthritis & Rheumatism, 65: 780–791. doi: 10.1002/art.37798
- Issue online: 25 FEB 2013
- Version of Record online: 25 FEB 2013
- Accepted manuscript online: 28 DEC 2012 11:29AM EST
- Manuscript Accepted: 8 NOV 2012
- Manuscript Received: 20 DEC 2011
- NIH. Grant Numbers: R03-AR-055778, P30-DK-079328-03, R01-AR-050812
Vol. 65, Issue 4, 1106, Version of Record online: 28 MAR 2013
To ascertain whether engineered expression of kallikreins within the kidneys, using an inducible Cre/loxP system, can ameliorate murine lupus nephritis.
In mice with a lupus-prone genetic background, we engineered the expression of tamoxifen-inducible Cre recombinase under the control of a kidney-specific promoter whose activation initiates murine kallikrein-1 expression within the kidneys. These transgenic mice were injected with either tamoxifen or vehicle at age 2 months and then were monitored for 8 months for kallikrein expression and disease.
Elevated expression of kallikrein was detected in the kidney and urine of tamoxifen-injected mice but not in controls. At age 10 months, all vehicle-injected mice developed severe lupus nephritis, as evidenced by increased proteinuria (mean ± SD 13.43 ± 5.65 mg/24 hours), increased blood urea nitrogen (BUN) and serum creatinine levels (39.86 ± 13.45 mg/dl and 15.23 ± 6.89 mg/dl, respectively), and severe renal pathology. In contrast, the tamoxifen-injected mice showed significantly reduced proteinuria (6.6 ± 4.12 mg/24 hours), decreased BUN and serum creatinine levels (15.71 ± 8.17 mg/dl and 6.64 ± 3.39 mg/dl, respectively), and milder renal pathology. Tamoxifen-induced up-regulation of renal kallikrein expression increased nitric oxide production and dampened renal superoxide production and inflammatory cell infiltration, alluding to some of the pathways through which kallikreins may be operating within the kidneys.
Local expression of kallikreins within the kidney has the capacity to dampen lupus nephritis, possibly by modulating inflammation and oxidative stress.