Renal tubule-specific expression and urinary secretion of human growth hormone: a kidney-based transgenic bioreactor growth.
Tissue-specific expression of human genes and secretion of human proteins into the body fluids in transgenic animals provides an important means of manufacturing large-quantity and high-quality pharmaceuticals. The present study demonstrates using transgenic mice that a 3.0 kb promoter of the mouse Tamm-Horsfall protein (THP, or uromodulin) gene directs the specific expression of human growth hormone (hGH) gene in the kidney followed by the secretion of hGH protein into the urine. hGH expression was detected in renal tubules that actively produce the THP, that is, the ascending limb of Henle's loop and distal convoluted tubules. Up to 500 ng/ml of hGH was detected in the urine, and this level remained constant throughout the 10-month observation period. hGH was also detectable in the stomach epithelium and serum in two of the transgenic lines, suggesting position-dependent effects of the transgene and leakage of hGH from the site of synthesis into the bloodstream, respectively. These results indicate that the 3.0 kb mouse THP promoter is primarily kidney-specific and can be used to convert kidney into a bioreactor in transgenic animals to produce recombinant proteins. Given the capacity of urine production independent of age, sex and lactation, the ease of urinary protein purification, and the potentially distinct machinery for post-translational modifications in the kidney epithelial cells, the kidney-based transgenic bioreactor may offer unique opportunities for producing certain complex pharmaceuticals.
Zhu
Xinhua
X
Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
Cheng
Jin
J
Huang
Liwei
L
Gao
Jin
J
Zhang
Zhong-Ting
ZT
Pak
Joanne
J
Wu
Xue-Ru
XR
D000818:Animals; D019149:Bioreactors; D005455:Fluorescent Antibody Technique; D013006:Growth Hormone / Q000652:urine*; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
D013006:Growth Hormone