Zavadil, Dickman, Grollman

We have recently established the role of aristolochic acid (AA) in the etiology of endemic (Balkan) nephropathy, a devastating disease marked by proximal tubule injury, tubulo-interstitial fibrosis and upper urothelial (transitional cell) carcinoma. In collaboration with Markus Bitzer (Albert Einstein College of Medicine) and Djuro Josic (Brown University), we integrate high throughput genomics and proteomics techniques with bioinformatics to explore the pathogenesis of aristolochic acid nephropathy (AAN). We have developed a mouse model that exhibits - in an accelerated fashion – the key histopathologic features of AAN (Fig. 1). At the molecular level, nephrotoxic responses to AA involve programs of p53-mediated DNA damage response and DNA repair, depletion of mitochondrial genes and renal tubular markers, necrotic and apoptotic cell death, and inflammatory and immune response (NFkB and TNFα signaling). A TGF-β signaling pathway contributes via an EMT-like mechanism to tubulo-interstitial fibrosis. We have shown how certain oncogenic microRNAs, as direct targets of TGF-β/Smad pathway, contribute to EMT/fibrogenesis by a mechanism leading to increased matrix metalloprotease activity. Proteomic experiments, based on iTRAQ/MS identification of AAI-modulated proteins in cultured human proximal tubular cells, complement the genomic studies to generate a comprehensive view of gene regulation in AAN. This collaborative research thus leads to discoveries of gene regulatory and signaling pathways underlying AAN (Fig 2), and identifies candidate molecular targets for therapeutic strategies against renal epithelial injury and fibrosis.

• Grollman, A. P., S. Shibutani, M. Moriya, F. Miller, L. Wu, U. Moll, N. Suzuki, A. Fernandes, T. Rosenquist, Z. Medverec, K. Jakovina, B. Brdar, N. Slade, R. J. Turesky, A. K. Goodenough, R. Rieger, M. Vukelic, B. Jelakovic,  Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 104: 12129-12134, 2007. 
• Zavadil, J., M. Narasimhan, M. Blumenberg, R. J. Schneider (2007). TGF-β and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 185: (in press). 
•  Zavadil, J., M. Bitzer, D. Liang, Y. C. Yang, A. Massimi, S. Kneitz, E. Piek, E. P. Bottinger,  Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci U S A 98: 6686-6691. 2001
  

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