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9.12.2011

Nephrologists Discover Key to Kidney Disease Progression

The Miller School’s Jochen Reiser, M.D., Ph.D., chief of the Division of Nephrology and Hypertension, has made another important discovery in the fight against progressive kidney disease, this one published in the September 12 online edition of The Journal of Clinical Investigation. Conducted with a research team at Harvard Medical School, the study explains why podocyte cells, which form the kidney filtration apparatus, often die after initial injury, increasing protein leakage into the urine and scarring of the kidneys.

Reiser, the study’s senior author who is also professor and vice chair for research in the Department of Medicine, and Sanja Sever, Ph.D., co-corresponding author and assistant professor of medicine at Harvard, specifically found that the protein dendrin is the transcription factor that promotes sustained expression of the protease cathepsin L, which the authors previously showed injures the podocyte structure and causes proteinuric kidney disease.

Slated to appear in the journal’s October print issue, the study, “CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival,” defines the critical link between the first injury of the cells (proteinuria) and the worsening of kidney disease caused by podocyte cell death.

The highly specialized podocytes produce the kidney filter membrane, or slit diaphragm, which is made up of numerous proteins and anchored at the plasma membrane. In addition to serving as a molecular sieve, the intact slit diaphragm promotes cellular survival of podocytes.

What had been uncertain and is now clarified by the collaboration between the Reiser lab and the Sever lab is the molecular mechanism that reduces the survival of podocytes when, under disease conditions, the slit diaphragm is disrupted. The authors found that the slit diaphragm protein CD2AP and the protein dendrin are linked, but only when the slit diaphragm is functional and intact. When the slit diaphragm is injured, for example by focal segmental glomerulosclerosis (FSGS), CD2AP is cleaved and releases dendrin, triggering the translocation of dendrin into the podocyte nucleus and the transcription of cathepsin L protease that causes progressive renal disease.

“We knew that proteinuria is a risk for more and progressive renal disease, but now we understand a mechanism for how this is occurring. A healthy filter membrane regulates a healthy transcriptional program—both of which are altered in disease,” Reiser explained. “The idea to improve not only proteinuria by rebuilding the slit diaphragm of podocytes, but also improve podocyte survival opens novel concepts for nephroprotection in otherwise progressive renal diseases, such as FSGS.”

Reiser and Mehmet M. Altintas, Ph.D., assistant professor of medicine and the study’s co-first author, expressed deep pride that the study was made possible by the years-long collaboration between the Reiser and Sever labs.

“This is what modern science is about,” Altintas said. “This study is the fruitful conclusion of multiple years of work and I am very curious to see if we can learn in the future how to abrogate dendrin signaling in the podocytes to help protect the cells.”

This study comes on the heels of another pivotal study Reiser and Changli Wei, M.D., Ph.D., assistant professor of medicine in the Division of Nephrology and Hypertension, published in the July 31 edition of Nature Medicine, which for the first time identified the circulating factor known to start the process of FSGS. Wei and Reiser led the international team that discovered that a soluble form of the urokinase plasminogen activator receptor (suPAR) is the long-sought circulating factor triggering glomerular kidney disease.

Each study represents another strike against chronic kidney disease. “The first study gives us the cause of chronic kidney disease, and this one lets us understand why the cells do not get better when they are injured,’’ Reiser said. “When the transcription factors are turned on as a consequence of the injured filter structure, podocytes are basically rendered for death, promoting the progression of kidney disease. Understanding this connection now lets us design novel strategies not only against proteinuria, but for cell survival.”

In addition to Reiser, Altintas and Wei, other co-authors of the Journal of Clinical Investigation study from the Miller School’s Division of Nephrology and Hypertension include: Andreas Kistler, M.D., Ph.D., research fellow; Isabel Fernandez, research technician; Vasil Peev, M.D.; Anna-Lena Forst, visiting student; Jing Li, lab manager; and Christian Faul, Ph.D., assistant professor of medicine; and from the Department of Surgery, Phillip Ruiz, M.D., Ph.D., professor of surgery and medical director of transplant laboratories.

Researchers at the Karolinska Institute in Stockholm, Sweden, the Hannover and Freiburg Medical Schools in Germany, the University of Michigan, the Renal Research Pathology Laboratory in Milan, Italy, and Washington University School of Medicine also contributed.

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