> Nephrotic Syndrome <

>Normal Glomerular Structure <

> Glucocorticoids <

> Podocytes <

My name is Richard Ransom, and I work at Nationwide Children's Hospital in Columbus, Ohio. I'm a Principal Investigator at the NCH Research Institute, and also an Assistant Professor in the Department of Pediatrics at The Ohio State University School of Medicine.

My laboratory's main area of investigation is the mechanism of action of glucocorticoids in the common children's kidney disease, nephrotic syndrome. Nephrotic syndrome is characterized by a disruption of the kidney's filtration barrier, which is contained within a globular structure called the glomerulus. The result of this disruption is the appearance of large amounts of blood proteins in the urine, which leads to edema as water moves from the protein-depleted blood plasma into the surrounding tissues. One of the cells within the glomerulus, the podocyte, is the only cell type in the body that appears abnormal in the most common form of nephrotic syndrome (minimal change nephrotic syndrome).

The primary therapy for nephrotic syndrome is oral glucocorticoids, and this therapy is typically very efficacious, leading to complete remission. However, a significant fraction (~20%) of patients either fail to respond to glucocorticoid therapy (steroid resistant), require glucocorticoid therapy to maintain remission (steroid dependent), relapse back to disease frequently (frequent relapsers), or develop steroid resistance over time. Some doctors also treat steroid resistant patients with even higher doses of injected glucocorticoids.

For more than 30 years, glucocorticoids have been hypothesized to work in nephrotic syndrome by suppressing the release of cytokines by specific white blood cells (T-lymphocytes). This hypothesis was first put forward by Shalhoub (Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556-60), and it remains the dominant paradigm for treatment despite the failure of extensive research to identify the cytokine(s) responsible for nephrotic syndrome. My laboratory's approach to understanding the mechanism of action of glucocorticoids in nephrotic syndrome is along two major lines of investigation. The first, supported by the NIH-NIDDK R01 grant #DK075533 and previously by the NIH-NIDDK R21 grant # DK064793, operates under the novel hypothesis that glucocorticoid therapy acts in nephrotic syndrome, at least in part, via a direct effect on glomerular podocytes. Work done under the R21 grant used a proteomic analysis to identify alterations in protein expression induced in cultured podocytes after glucocorticoid treatment, and the ongoing studies pursued under the R01 grant are intended to follow up on the proteins identified in the proteomic analysis and to produce transgenic mice that can be used to definitively test the hypothesis that glucocorticoids exert at least a portion of their action directly on podocytes during nephrotic syndrome.