Drug Discovery By University Of Miami Experts Will Lead To Better Treatments For Kidney Disease

Main Category: Urology / Nephrology
Article Date: 27 Aug 2008 - 1:00 PDT

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Nephrology physician-scientists at the University of Miami Miller School of Medicine have discovered a critical pathway of a commonly used immunosuppressant drug, cyclosporine. The finding, made by Peter Mundel, M.D., professor and director of the Miami Institute of Renal Medicine, Christian Faul, Ph.D., assistant professor of medicine in the Division of Nephrology and Hypertension, and Jochen Reiser, M.D., Ph.D., professor of medicine and chief of the Division of Nephrology and Hypertension, will make it possible to identify drugs that hold the benefits of cyclosporine in treating kidney disease, without its long-term ill effects.

The discovery has been published in the September issue of the premiere research journal Nature Medicine.

The scientists, who recently left Mount Sinai School of Medicine and Harvard Medical School to join the Miller School, have shown a completely new mechanism for the reduction of urinary protein loss by cyclosporine A (CsA). Cyclosporine A is known as an immunosuppressant drug used in organ transplantation for its ability to inhibit T cell function through the inhibition of calcineurin signaling. It is also used in kidney disease to treat patients who have protein in the urine, a condition that is, among others, a serious risk for cardiovascular death.

In many kidney diseases, it is common to see the dysfunction of podocytes, cells that live in the lining of the kidney which are responsible for filtering protein. When the podocyte function breaks down, there is a massive loss of protein in the urine, a condition known as proteinuria.

For many years, scientists believed that cyclosporine's antiproteinuric effect centered on its ability to shut down the signaling of T cells, just as it does as an immunosuppressant. Instead, the research by the three UM scientists and nine other researchers indicates that cyclosporine works as an antiproteinuric due to its direct effect on the podocyte actin cytoskeleton.

"Our research shows a new mechanism," says Mundel, the study's principal investigator. "This finding has big clinical implications." He explains that scientists now have a new avenue for finding new drugs that avoid the side effects of long-term use of cyclosporine in treating kidney disease, which can include the loss of kidney function itself.

Mundel says doctors often don't understand how prescribed drugs actually work on patients. "This study not only describes the mechanism of cyclosporine in the kidney," says Mundel, "it also sheds light on the pathogenesis of proteinuric diseases in general, suggesting that the immune system is much less important for this type of disease than anticipated." Mundel says this understanding has great potential to treat proteinuria. Most importantly, synaptopodin, a protein Mundel has been working on for more than two decades, was found in this study to be a direct target of cyclosporine. This discovery will allow researchers to develop novel antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.

This is the second article from this new group of UM nephrologists published in Nature Medicine within eight months. In a previous study led by Reiser (Wei et al. Nat Med. 2008 Jan; 14(1):55-63.), they showed that functions of podocytes can be directly modified in a positive way by novel experimental drugs, a discovery that could lead to patient use very soon.

Reiser sees these two studies as solid building blocks for their work ahead. "We have found that these new discoveries will allow us to find new drugs to treat proteinuria and more effectively help our patients in the near future," says Reiser. The Division of Nephrology and Hypertension recently established the Miami Institute of Renal Medicine, which houses a Drug Discovery Center that will focus on the development of kidney-specific drugs. "We are very excited to be here," says Reiser, "working in a team effort to turn our research into practical applications that benefit patients."

University of Miami Miller School of Medicine