A novel mouse model of kidney fibrosis induced by glomerulus‐specific overexpression of the full‐length of human transforming growth factor‐β1 gene

Abstract

Chronic renal disease is a common complication of several diseases including diabetes mellitus, hypertension and chronic glomerulonephritis. Approximately 10% of adults in developed countries suffer from chronic renal disease. Clinical progression of chronic renal disease leads to end‐stage renal disease that can be treated only with renal replacement therapy including dialysis and renal transplantation. There is currently no other therapeutic option for patients in terminal stages of the disease. The main reason of the scarce therapeutic strategies for this chronic and fatal disease is the lack of appropriate disease model to evaluate drug discovery. In the present study, we focused on the potent profibrotic activity of transforming growth factor‐β1 and its critical mechanistic role in glomerulosclerosis. We prepared and amplified a chimeric mouse podocin/human transforming growth factor‐β1 bacterial artificial chromosome construct, purified, linearized, separated by pulsed field gel electrophoresis and dialyzed before microinjection into fertilized eggs. We obtained several founders expressing the transgene as demonstrated by Southern blotting. As expected, the transgenic mice have increased plasma levels of human transforming growth factor‐β1, creatinine and blood urea nitrogen from 8‐weeks of age. The urine levels of fatty acid‐binding protein, a marker of kidney injury, and human transforming growth factor‐β1 were also significantly increased in the transgenic mice compared to wild type mice. Trichrome staining of the kidneys disclosed extensive deposition of extracellular matrix proteins in the transgenic mice compared to their wild type counterparts. In addition to highlighting the important role of transforming growth factor‐β1 in the pathogenesis of kidney fibrosis, the results of this study led to development of a novel mouse model of kidney fibrosis that may be useful for drug discovery.Support or Funding InformationI have no financial relationships to disclose.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.