Roy Zent, M.D., Ph.D., right, with collaborator Reinhard Fässler, M.D., of Germany’s Max Planck Institute of Biochemistry.
Cell-matrix interactions key to kidney development
During development, organs including the kidney and lungs develop by “branching” out from a central tube of cells, like the limbs of a tree. Interactions between the cells and the material that surrounds them — the extracellular matrix — regulate this branching growth.
Vanderbilt investigators, with collaborators in Germany, have discovered that the cellular receptor beta-1 integrin, which interacts with components of the matrix, and a protein called integrin-linked kinase, have critical roles in the developing mouse kidney. Their findings, reported in two papers in Development and Nature, offer new insights to how the kidney develops, a process that can go awry and lead to kidney failure.
“We really don't know very much about the mechanisms that cause defects in kidney development,” said Roy Zent, M.D., Ph.D., associate professor of Medicine. “Our studies of the branching and how it's regulated will lead to a better understanding of what can go wrong.”
Zent and a “large and dynamic” group of investigators in the Vanderbilt Center for Matrix Biology are unraveling the connections between the cell and the extracellular matrix. They study cell-matrix interactions using biochemistry, cell biology, and structural biology approaches.
About six years ago, a chance interaction between Zent and Reinhard Fässler, M.D., director of Molecular Medicine at the Max Planck Institute of Biochemistry in Martinsried, Germany, led to a productive collaboration. The two realized that they were both exploring the same types of questions, but in different organs.
“Fässler's group was focused on skin, the hemopoietic system and bones while we were interested in the kidney, so it was a great match,” Zent said.
Together, the two groups have created a series of mouse models with altered integrins (receptors that attach a cell to the matrix) and integrin-related proteins.
To study the role of integrin signaling in the kidney, they deleted beta-1 integrin specifically in the developing kidney at two time points — at the time of initiation of kidney development and late in development, just before birth. Deletion of the receptor at the early time disrupted branching and kidney development. Interestingly, Zent said, the beta-1 integrin was required not just for cell adhesion to the matrix, but also for growth factor signaling.
“That's probably why there's a really bad outcome if the receptor is missing during the rapid branching phase of development,” he said.
The kidneys in mice missing beta-1 integrin at the later time point were relatively normal, Zent said, but they were more susceptible to severe fibrosis in a model of kidney injury. The investigators are now exploring whether beta-1 integrin plays a role in repair mechanisms following kidney injury.
The researchers also studied the role of integrin-linked kinase during development by making small changes to the gene in mouse models. One particular change that altered the interaction of integrin-linked kinase with another protein caused kidney defects — including the absence of kidneys.
The team showed that in vivo, integrin-linked kinase does not function as a kinase, an enzyme that adds chemical groups called phosphates onto proteins. Instead, it appears to be important in the formation of a signaling hub.
The research was supported by the National Institutes of Health, the American Heart Association, a Merit award from the Department of Veterans Affairs, the NIH George O'Brien Center Grant and the Max Planck Society.
For more information about the Center for Matrix Biology, please go to www.mc.vanderbilt.edu/cmb/.