Progressive scarring of the kidneys is the poorest outcome of kidney diseases, requiring dialysis and kidney transplantation. Scarring often focuses on the glomerulus, the filtering unit of the kidney. Although recent mouse recombinant technology has brought about many ground-breaking discoveries in biomedical research, we have not been able to take advantage of this powerful technology to study glomerular scarring because the mouse is a species uniquely resistant to developing progressive glomerular diseases. Over the last several years, the PI has invested the majority of his research effort to overcoming this hurdle by designing and engineering several unique mutant mouse models. Thus, we now have 1) mutant mice in which progressive glomerular disease can be induced at a time, speed and in severity of our choice, by selectively damaging podocytes, a key cell that is, initially injured in a variety of human glomerular diseases. We also have 2) unique mutant mice, """"""""chimera"""""""", in which disease is induced only in a portion of the glomerulus so that we can investigate how disease spreads from cell to cell, and 3) mutant mice lacking the receptor for angiotensin (a notorious offender in glomerular diseases) selectively in the podocyte so that we can study how angiotensin causes progression of glomerular diseases. Of note, angiotensin inhibitors are the only class of drugs that have clinically proven to be effective in attenuating, although not completely halting, progressive glomerular scarring. Most recently, we have observed remarkable protection against injury in our mutant models when kidney work (that is, filtration) was transiently put to rest. The PI therefore believes that the study into these models will not merely document the dying process of scarring glomeruli, but instead, will identify the clue to the effective measure of intervening the process of glomerular scarring.
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