Our laboratory studies the intracellular signals that mediate fibrosis in progressive kidney disease. We use as our model several different types of cultured kidney cells. These include human and mouse mesangial cells, which occupy a central location in the filters of the kidney, where they provide a support structure for the blood vessels entering the filter (also known as the glomerulus). Mesangial cells also may play a role in regulating the local production of soluble mediators that regulate many aspects of local cell function.
We also study cells from the kidney tubules that reabsorb much of the fluid filtered by the kidney and are located where kidney scarring takes place. Finally, our lab members study fibroblasts, the cells that make much of the connective tissue in the kidney and elsewhere. To learn how these cells function in health and disease, we change the chemicals and hormones that might activate the cells, the local microenvironment determined by proteins to which the cells are attached, and the genes that are activated to express proteins in the cells.
Normally, there is a small amount of connective tissue, the extracellular matrix (ECM) – including collagen, laminin and other structural proteins – around the mesangial cells and the blood vessels. In the disease focal segmental glomerulosclerosis (FSGS), the ECM accumulates, starting in the region around the mesangial cells.
The central question guiding our work is: how does a fibrogenic hormone called transforming growth factor (TGF-beta) stimulate excessive ECM production by the mesangial cell?
The immediate intracellular mediators are molecules that are members of the Smad signal transduction family. TGF-beta binds to its cognate receptor, which then activates the Smads to aggregate. The Smad complex is transported to the nucleus where it participates in the transcriptional activation of genes that encode for ECM and other proteins. Although the Smads are the only signaling molecules that the TGF-beta receptors are known to activate directly, we and other researchers have identified many other signaling pathways that are activated in mesangial cells after TGF-beta stimulation.
In studies supported by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), we have determined that some of these other pathways play a significant role in TGF-β-activated collagen production. Currently, we are investigating the mechanism by which these other pathways are activated and how cross-talk among the pathways influences ECM gene expression. Our lab has focused on the roles of three proteins that regulate some aspect of Smad-mediated collagen expression:.
- Molecules called integrins that cells use to attach to surfaces and that also propagates chemical signals in the cell
- A TGF-β receptor adaptor molecule called Smad Anchor for Receptor Activation (SARA) that helps determine the functional responses of cells
- The signaling molecule, ERK MAP kinase, which modulates the activity of Smad3 differently in different cells
Recently, we also have begun to investigate a fourth molecule, HIF-1α, which also seems to play an important role in ECM production by mesangial cells. These molecules interact with numerous other signals in the cell (see diagram in Figure 3).
Figure 2. Non-canonical Smad signaling in TGF-β-stimulated mesangial cell collagen expression. Integrins interact with focal adhesion kinase (FAK) and the Rho GTPase Rac1 to promote ERK activation and subsequent phosphorylation of the Smad3 linker region. Protein kinase (PK)Cd also may activate ERK. SARA affects the balance between Smad2 and Smad3 signaling; its loss promotes fibrogenic responses by the cell. HIF-1α interacts with the collagen promoter and with Smad3 activity to further promote fibrogenesis.
By understanding these interactions, we hope to identify ways to interrupt the signals that mediate ECM accumulation, and slow the scarring process in kidney disease.
H. William Schnaper, MD
Department of Pediatrics
Morton 4-685G (MS# W-140)
310 E. Superior St.
Chicago, IL 60611-3008
Following are links to more information to entities and areas of focus related to the Schnaper lab.
- Department of Pediatrics
- Lurie Children’s Division of Kidney Diseases
- Driskill Graduate Program (DGP) in the Life Sciences
- Northwestern University Clinical and Translational Sciences Institute
- Children’s Hospital of Chicago Research Center
- American Society of Pediatric Nephrology
- American Society of Nephrology