Scientists at the Saban Research Institute at The Children’s Hospital Los Angeles have shown that stem cells from amniotic fluid can slow kidney disease progression in mice with Alport syndrome. Treating the mice with stem cells prior to the onset of proteinuria improved survival rates, delayed the progression of kidney scarring and lessened the decline in kidney function. Although the treatment did not result in new podocyte-like cells due to stem cell differentiation, normal podocyte numbers were preserved. The researchers think the protective benefits of stem cells may be due to inhibition of the renin-angiotensin system. They believe amniotic stem cells could be beneficial in treating other fibrotic kidney diseases, but they don’t know whether they could help with chronic kidney disease.

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Injection of Amniotic Fluid Stem Cells Delays Progression of Renal Fibrosis, Journal of the American Society of Nephrology, February 2, 2012

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Scientists studying the mechanisms behind cell adhesion have made some significant discoveries about the factors that influence podocyte survival. The kidney filter barrier is made up of podocyte cells with long foot-like projections that wrap around the capillaries of the glomerulus. The slits between these projections allow smaller molecules like salts, water and sugar to pass, while preventing larger molecules such as proteins from leaving the blood stream. Podocytes undergo significant physical stress as blood is pushed through the filter barrier. A receptor called integrin a3ß1 ensures that podocyte cells remain tightly bound to the glomerular basement membrane.

Researchers from the Netherlands Cancer Institute in Amsterdam explored the link between a3ß1 and a protein called CD151, which is strongly expressed in podocytes.  They showed that CD151 and a3ß1 interact and that CD151 is involved in adhesion strengthening.  They studied mice lacking CD151 in podocytes and discovered that the mice developed glomerulosclerosis. They also suffered from kidney abnormalities, including unusually broad foot processes and irregular thickening of the glomerular basement membrane. They found that mice lacking global CD151 were not necessarily susceptible to renal disease unless they had a genetic predisposition. They reasoned that because the mice lacked CD151, their podocytes would be more loosely bound and unable to withstand increased mechanical stress. They proved the theory by increasing blood pressure and filtration pressure, which induced nephropathy in the mice.  Treating the mice with an ACE inhibitor drug reduced blood pressure as well as pressure within the glomerulus and prolonged their life span. The scientists determined that the reduction in glomerular pressure was key to preserving podocytes and slowing down glomerulosclerosis in the mice.

Source:

Blood Pressure Influences End Stage Renal Disease of CD151 Knockout Mice, Journal of Clinical Investigation, January 3, 2012

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Researchers at Stanford School of Medicine have discovered that the podocyte cells that make up the kidney filter membrane may be able to regenerate during normal kidney function. Scientists have long believed that these cells, which suffer damage in more than 90 percent of chronic kidney diseases, such as FSGS and diabetic nephropathy, could not renew themselves. Researcher Steven Artandi, M.D., Ph.D., said, “It used to be thought that you were born with podocytes, and died with the same podocytes—you don’t make any more during your lifetime.”

In this study, Artandi and fellow scientists found that the over-expression of TERT, a protein component of the enzyme telomerase, causes podocytes to de-differentiate and divide, and the glomeruli to collapse as a result. A similar scenario occurs in patients with HIV-associated nephropathy or HIVAN. Interestingly, examination of the glomeruli of HIVAN patients revealed increased expression of TERT. Experiments in lab mice showed that increasing the expression of TERT produced the same result as in humans; once over-expression ceased, the cells stopped dividing and began acting like specialized podocyte cells again. The researchers also found that the Wnt signaling pathway is activated in patients with HIVAN. Wnt proteins are important to embryonic development and cell differentiation. The scientists were able to block Wnt signaling in mice with HIVAN to stop podocyte division and improve function. They now hope to discover if podocyte regeneration occurs during healthy kidney function. Dr. Artandi said, “If we can harness this regeneration, we may one day be able to treat people with chronic kidney disease.”

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Regeneration of Specialized Cells Offers Hope for Treating Chronic Kidney Disease, Researchers Say, Stanford School of Medicine, December 4, 2011

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Researchers at University of Miami Miller School of Medicine and Harvard Medical School have discovered an important molecular mechanism behind worsening kidney disease. In a disease such as FSGS, for example, the kidney filter membrane (also known as the slit diaphragm) is damaged, allowing proteins to leak into the urine. The initial damage causes further injury to the podocyte cells, which make up the filter membrane. The podocytes die, resulting in more proteinuria and scarring of the kidneys.  The researchers found that when filter membrane injury occurs, CD2AP—a protein important for podocyte survival and proper signaling in the filter membrane—splits and releases the protein dendrin. This increases activity of protease cathepsin L, or Catl, which then degrades CD2AP, continuing the cycle of damage.

The study’s senior author, Jochen Reiser, M.D., Ph.D., explained, ““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. 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.”

Sources:

Nephrologists Discover Key to Kidney Disease Progression, University of Miami Miller School of Medicine, September 12, 2011

CD2AP in Mouse and Human Podocytes Controls a Proteolytic Program That Regulates Cytoskeletal Structure and Cellular Survival, JCI, The Journal of Clinical Investigation, October 3, 2011

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Kidney podocytes (shown in yellow) wrapping around the capillaries of the glomerulus

Researchers at University of Miami Miller School of Medicine, collaborating with a team of doctors and surgeons, have uncovered how the drug Rituximab, normally used to treat non-Hodgkin’s lymphoma, rheumatoid arthritis, and chronic lymphocytic leukemia, also works to prevent FSGS from recurring in children and young adults with kidney transplants. The drug appears to bind to and preserve a protein (SMPDL-3b) on kidney podocytes. The protein is under-expressed in patients with recurring FSGS. Rituximab stabilizes protein expression, protecting the fiber formation and structure of the podocytes and preserving their filtering ability. One dose of the drug appears to improve kidney function for up to 12 months.

This could greatly impact the 80% of FSGS patients who experience a recurrence of the disease after kidney transplantation. The discovery may help scientists predict which patients are at risk of a recurrence and provides them with vital clues for understanding the cause and development of FSGS at the molecular level.

Source:

Physicians Discover How Cancer Drug Works to Help Prevent Recurrent Kidney Disease, University of Miami, Miller School of Medicine, June 1, 2011

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