Approximately 14% of the US population is affected by chronic kidney disease (CKD), and roughly 4.5 million patients currently require dialysis. An additional 2 million patients live with transplantation to supplement kidney function lost due to CKD.
A kidney consists of ~ 1 million filtration units called glomeruli. Glomeruli are basically a ball of capillary blood vessels, supported by specific epithelial cells called podocytes, to create a fine sieve to filter circulating blood. This permits the kidney to excrete excess electrolytes, water and toxins while retaining serum proteins. While many conditions could lead to CKD, glomerulopathy, injury to this filtering structure is the major primary cause for CKD in both adults and children.
Our lab studies mechanisms by which glomerulopathy progresses, with two major points of potential therapeutic intervention: podocyte injury and activation of fibrogenesis (FIG 1).
Although dozens of genetic mutations have been identified in association with glomerulopathy, in the majority of cases, the etiology is unknown.
Many pathways have been suggested to mediate podocytes injury. We recently found that p110g, a catalytic subunit of the g isoform of PI3-kinase, could be a mediator of podocyte injury for many distinct etiologies. Unlike the ubiquitously-expressed, well-studied a and b isoforms, the g isoform of PI3-kinase is primarily expressed in inflammatory cells. We showed that this isoform is upregulated in podocytes of mice subjected to a stimulus that causes glomerulopathy, and that a specific inhibitor of p110g prevents injury to podocytes (Fig 2).
The g isoform of PI3-kinase is unique not only in its distribution, but also in its mode of activation, utilizing G-protein coupled receptors and two distinct regulatory subunits. The exact mechanisms by which this isoform mediates podocyte injury, as well as its relevance to human disease, are topics of active investigation in the lab. Specific inhibitors of p110g are under development by pharmaceutical companies for cancer treatment, anticipating possible application of such drugs in treating or preventing injury to podocytes.
ACTIVATION OF SCAR-FORMING CELLS
From the initial presentation, it usually takes 5 to 10 years for patients with glomerulopathy to progress to the final stages of CKD and complete loss of kidney function. The main pathologic mechanism of failing kidneys is fibrosis; that is, tissue scarring.
Intracellular signals that mediate fibrosis have been the major focus of the lab over the past two decades, with stimulation by the well-known fibrogenic cytokine, transforming growth factor b (TGF-b), as a central focus. When mice with glomerulopathy are treated with an inhibitor to TGF-b, fibrotic tissue formation is prevented, as expected, while proteinuria, as a result of podocyte injury, persists (Fig 3). These data indicate that the mechanism for fibrosis is distinct from that of podocyte injury, and that scar formation is another potential therapeutic target even at the stage where podocyte injury is irreversible. We have explored several important modulators of TGF-b signaling specific to fibrogenesis.
Most cells in the kidney have specific characteristics that determine their function, and are said to be “differentiated.” Maintenance of a differentiated state depends upon the local tissue structure and many molecules within and outside of the cell. When cells are exposed to fibrogenic stimuli such as TGF-b, they change their characteristics and become scar producers. Our laboratory has found that a molecule inside the cell called SARA (Smad Anchor for Activation) may help prevent this from happening. Epithelial cells are low in scar-forming capability and express a lot of SARA. When either exposed to TGF-b or genetically depleted of SARA, they start expressing markers for activation and produce scar material (Runyan, J BIol Chem, 2009). Interestingly, fibroblasts, which produce scar tissue, do not express SARA. Recent experiments in our lab suggest that SARA might prevent cells from contributing to some forms of fibrosis (unpublished). Together, these data implicate SARA in maintenance of non-fibrotic cell phenotype, and therefore could be an anti-fibrotic molecule.
The project aimed at better understanding how SARA works has recently been funded by the National Institute of Diabetes and Digestive and Kidney Disease.
Recent publications (selected)
- Liang X, Schnaper HW, Matsusaka T, Pastan I, Ledbetter S, Hayashida T: Anti-TGF-b antibody, 1D11, ameliorate glomerular fibrosis in ouse models after the onset of proteinuria. Plos One, http://dx.doi.org/10.1371/journal.pone.0155534, 2016
- Baumann B, Hayashida T, Liang X, Schnaper HW; HIF-1a promotes glomerulo-sclerosis and regulates COL1A2 expression through interactions with Smad. Kidney Int, 90(4):797-808, 2016 [PMCID: PMC5026582]
- Finer G, Schnaper HW, Kanwar YS, Lin HY, Hayashida T; Divergent roles of Smad3 and PI3- kinase in murine Adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis. Kidney Int, 82, 525-536, 2012
Research Associate Professor of Pediatrics (Kidney Diseases)
Tomoko Hayashida, MD, PhD
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