Signaling Pathways in Renal Fibrogenesis

  • Hayashida, Tomoko (PD/PI)
  • Mishra, Rama K (Other)

Project: Research project

Project Details


Approximately 2.5 million people suffer from advanced chronic kidney disease (CKD) in the United State, among whom 60-100,000 lose kidney function each year, needing dialysis and/or transplantation. CKD often progresses from an initial disease where the filtration units in the kidney, the glomeruli, are damaged, causing plasma proteins to leak into the urine (proteinuria). The podocyte is a unique cell in the glomeruli, one that is critical for the intact kidney filter. We recently reported that, in a mouse model of chemically induced glomerular disease, levels of a signal transduction molecule called PI3K are very high. Inhibiting PI3K prevented podocyte damage and proteinuria. Subsequent kidney scarring that is the direct cause of kidney loss was also prevented. We grew podocytes from mice, and the inhibitor also prevented podocyte shape change and cell death after injury in the cultured podocytes. We then looked at human kidney biopsies from patients with proteinuria and found that glomerular PI3K expression is increased in patients with a scarring glomerular disease (FSGS), but not with non-scarring minimal change disease. Together, our data suggest that PI3K mediates podocyte damage and therefore is a potential therapeutic target, leading us to submit a grant application for federal funding last fall. The proposal was favorably reviewed but not funded. In order to prepare a stronger, revised proposal, we request IGA program support, with the following three aims: First, we will perform studies to more directly relate PI3K activity in cultured podocytes to cell-regulatory systems described by others as being important in maintaining podocyte shape. These studies will enhance the perceived relevance of our findings to the general field of podocyte biology. Second, we will characterize a new mouse model of glomerular disease, as it is imperative to determine whether targeting PI3K is a possible therapeutic approach to human disease. We will test PI3K activity in mice with transgenic inactivation of the gene for podocin. The podocin gene is the one most commonly mutated in childhood FSGS. We recently obtained Nphs2-Cre mice from a collaborator, in which podocin can be deleted in an inducible manner. We will confirm that this mouse demonstrates proteinuria and kidney scarring as was originally described, and determine whether PI3K expression is increased in a manner consistent with its having a role in proteinuria. Third, we will seek to develop a novel chemical inhibitor of PI3K, in collaboration with the Center for Molecular Innovation and Drug Discovery of Northwestern University. The compound that we used in our original report is reasonably well tolerated but shows some toxicity in mice. Therefore, the development of a new, safe and efficient compound is critical for potential use in humans. Data we obtain from these proposed studies will strongly support a revised R01 grant application by strengthening our preliminary data, increasing the novelty of our studies, and offering the possibility of a new therapeutic approach to preventing kidney loss in proteinuric kidney disease.
Effective start/end date4/1/159/30/16


  • Ann & Robert H. Lurie Children's Hospital of Chicago (925535-NU)


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