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Calcineurin A-alpha Plays a Key Role in the Development of Renal Fibrosis
Research Day
  • Jennifer L. Gooch, Philadelphia College of Osteopathic Medicine
  • Yun Bai, Philadelphia College of Osteopathic Medicine
Location
Georgia Campus
Start Date
7-5-2014 1:00 PM
Description

Calcineurin is a cellular phosphatase that is activated by calcium in a wide variety of normal and diseased conditions. For example, calcineurin is required for heart and kidney development and in the immune system. Calcineurin is also important for normal kidney development and function. Clinically, drugs that inhibit calcineurin are used clinically to treat conditions that involve increased immune responses and to prevent rejection following organ transplantation. Unfortunately, almost all individuals who receive calcineurin inhibitors (CNIs) for a prolonged period of time will develop side effects including kidney fibrosis and 10-15% of those patients will progress to renal failure, requiring dialysis or a kidney transplant. While some key features of CNI nephrotoxicity have been described, mechanisms of calcineurin action in the kidney are poorly understood. This is the focus of research in my laboratory. There are two main isoforms of the catalytic subunit of calcineurin – α and β – that have different physiological roles. We have shown that loss of α is sufficient to reproduce key aspects of CNI nephrotoxicity including upregulation of transforming growth factor β (TGFβ) and fibrosis. Recently, we reported that aged mice heterozygous for the α isoform (CnAα) develop progressive fibrosis and reduced kidney function that is ameliorated by neutralization of TGFβ. Reduced kidney function was related to an increase in intrarenal cell populations that express matrix proteins and alpha-smooth muscle actin (α-SMA); features that are hallmarks of myofibroblasts. Myofibroblasts are specialized cells that take up residence in the renal tubular interstitium (TI) in response to injury or disease and produce matrix proteins and cytokines and recruit lymphocytes. The degree of myofibroblast expansion in the TI is closely associated with progressive renal failure. Interestingly, upregulation of TGFβ and fibrosis are common in many forms of renal disease, suggesting that CnAα may function in a pathway that is fundamental to the health of the kidney. While TGFβ upregulation has long been recognized as a consequence of calcineurin inhibition, the role of CnAα in the development of myofibroblasts has not been investigated. The goal of this ongoing project is to define the mechanism of myofibroblast development with loss of CnAα in order to identify novel therapeutic targets. In particular, we will test the role of epithelial to mesenchymal transformation (EMT) in the development of myofibroblast expansion and TI fibrosis. Recent work shows that, in addition to increased TGFβ, loss of CnAα is associated with increased phosphorylation of NFkB. Transcriptional targets of NFkB include subunits of the NADPH oxidase and matrix metalloproteinases (MMPs), both essential proteins in epithelial to mesenchymal transformation. Our data show that CnAα-/- cells and tissue have increased reactive oxygen species production and Nox4 expression. In addition, we find increased expression of MMP9. These data support a role for CnAα in repression of EMT and suggest a new model for development of TI fibrosis.

Citation Information
Jennifer L. Gooch and Yun Bai. "Calcineurin A-alpha Plays a Key Role in the Development of Renal Fibrosis" (2014)
Available at: http://works.bepress.com/yun_bai/2/