Josh Lipschutz, M.D.
Assistant Professor of Medicine
University of Pennsylvania
415 Curie Boulevard
Clinical Research Building, 5th Floor
Fax: (215) 898-0189
Phone: (215) 573-1848
Undergraduate: Indiana University, Indianapolis, IN
Medical: Indiana University, Indianapolis, IN
Residency: Indiana University, Indianapolis, IN
Fellowship: University of California, San Francisco, CA
Board Certification: Internal Medicine and Nephrology
Dr. Lipschutz’s research involves kidney development, how this process goes awry in polycystic kidney disease and how it contributes to the recovery that follows acute kidney injury. In his basic science lab, these questions are examined at a cellular and molecular as well as a translational level.
Dr. Lipschutz has a military background as a physician in the Pennsylvania Army National Guard with active duty deployments to both Iraq and Afghanistan. He treats men and women who seek medical care at the Philadelphia VAMC where he is also the Chief of Nephrology.
Cystogenesis, Tubulogenesis, and Kidney Development
Cystogenesis and tubulogenesis are important for many complex biological processes such as organ development, regeneration following acute kidney injury (AKI), and diseases such as Autosomal Dominant Polycystic Kidney Disease (ADPKD). This lab has three basic experimental goals: first, to find novel genes involved in cyst and tubule formation using techniques such as DNA microarray analysis; second, to determine the molecular mechanism by which these candidate genes act using both in vitro and in vivo studies, such as the creation of transgenic and knockout mice; and, finally, to utilize this knowledge to identify treatment strategies for ADPKD and to accelerate recovery following AKI.
An example of a group of candidates’ genes for cyst and tubule formation, identified by the Lipschutz lab, is the exocyst complex. The exocyst is a highly conserved eight protein complex involved in the biogenesis of polarity in organisms as diverse as yeast and mammals. The exocyst is centrally involved in cystogenesis/tubulogenesis and acts by specifically modulated synthesis and delivery of basolateral plasma membrane and secretory proteins. One member of the exocyst complex, Sec 10, is particularly important in that it acts as a bridge between the vesicles that carry polarized proteins and the rest of the exocyst complex, which is found adjacent to the plasma membrane. Current studies are investigating how the exocyst acts at a cellular and molecular level and the role of exocyst complex in kidney development. Given the relatively ubiquitous expression of the exocyst complex in a variety of different cells and organs, the Cre-Lox system is being used to generate mice with a kidney-specific disruption in the Sec 10 gene.
Many diseases, such as ADPKD, involve reactivation of developmental programs. ADPKD is the most common potentially lethal monogenic disorder and affects 500,000 Americans alone. In the case of ADPKD, gigantic cystic structures form that ultimately results in the destruction of the kidney. Defects in ciliogenesis are central to the pathogenesis of ADPKD, and the Lipschutz Lab has recently shown that the exocyst is necessary for ciliogenesis and that the exocyst traffics polycystin-2 in vitro and in vivo. Polycystin-2 is the protein product of PKD2, one of two genes, which when mutated, causes ADPKD. Abnormalities in the exocyst complex have been demonstrated in tissue samples and cell lines derived from patients with ADPKD by this lab and others. In both yeast and mammals, the exocyst is controlled by the Rho family of small GTP-binding proteins. We have recently shown that Rho family proteins interact with the exocyst to regulate cyst and tubule formation, as well as ciliogenesis. Using a gold standard mouse model of ADPKD, the PKD2 25/183 mouse developed by the Somlo Lab at Yale, the Lipschutz Lab, in collaboration with the Bennett Lab at Penn, is using AAV-mediated gene therapy to treat ADPKD
For further information, see the Cell and Molecular Biology Graduate Group website: http://www.med.upenn.edu/camb/faculty/cbp/lipschutz.html
Zhang, X., Bi, E., Novick, P., Du, L., Kozminski, K.G., Lipschutz, J.H., and Guo, W. 2001. Cdc42 Interacts with the Exocyst and Regulates Polarized Exocytosis. Journal of Biological Chemistry. 276 : 46745-46750.
Rogers , K.K., Jou, T., Guo, W., Lipschutz, J.H. 2003. The Rho Family of Small GTPases is Involved in Epithelial Cystogenesis and Tubulogenesis. Kidney International. 63: 1632-1644.
Lipschutz, J.H., Lingappa, V.R., Mostov, K.E. 2003. The Exocyst Affects Protein Synthesis by Acting on the Translocation Machinery of the Endoplasmic Reticulum. Journal of Biological Chemistry. 278 (23): 20954-20960.
Balkovetz, D.F., Gerrard, Jr., E.R., Shixiong, L., Johnson, D., Lee, J., Tobias, J.W., Rogers, K.K., Snyder, R.W., Lipschutz, J.H. 2004. Gene Expression Alterations During HGF-Induced Dedifferentiation of a Renal Tubular Epithelial Cell Line (MDCK) Using a Novel Canine DNA Microarray. American Journal of Physiology, Renal Physiology. 286 F702-F710.
Rogers , K.K., Wilson, P.D., Zhang, X., Guo, W., Burrow, C.R., Lipschutz, J.H. 2004. The Exocyst Localizes to the Primary Cilium in MDCK Cells. Biochemical and Biophysical Research Communications. 319: 138-143.
O'Brien, L.E., Tang, K., Kats, E.S., Schutz-Geschwender, A., Lipschutz, J.H., Mostov, K.E. 2004. ERK and MMPs Sequentially Regulate Distinct Stages of Epithelial Tubule Development. Developmental Cell. 7:21-32.
Snyder, R.W., Ruhe, J., Kobrin, S., Wasserstein, A., Nachamkin, I., Lipschutz, J.H. 2004. Asaia Bogorensis Peritonitis, Identified by 16S Ribosomal RNA Sequence Analysis in a Patient Receiving Peritoneal Dialysis. American Journal of Kidney Diseases. 44: E15-17.
Berman, E., Merz, J.F, Rudnick, M., Snyder, R.W., Rogers, K.K., Lee, J., Johnson, D., Mosenkis, A., Israni, A., Wolpe, P.R., Lipschutz, J.H. 2004. Religiosity in a Hemodialysis Population and Its Relationship to Satisfaction with Medical Care, Satisfaction with Life, and Adherence. American Journal of Kidney Diseases. 44(3): 488-497.
Lipschutz, J.H., Li, S., Arisco, A., Balkovetz, D.F. 2005. Extracellular-Signal-Regulated Kinases 1/2 Control Claudin-2 Expression in Madin-Darby Canine Kidney Strain I and II Cells. Journal of Biological Chemistry. 280(5): 3780-3788.
Hellman, N.E., Greco, A.J., Rogers, K.K., Balkovetz, D.F., Lipschutz, J.H. 2005. Activated Extracellular Signal Regulated Kinases (ERKs) are Necessary and Sufficient to Initiate Tubulogenesis in Renal Tubular MDCK Strain I Cell Cysts. American Journal of Physiology, Renal Physiology. 289(4): F777-785.
Christensen, M., Su, A.W., Snyder, R.W., Greco, A., Lipschutz, J.H., Madaio, M.P. 2006. Simvastatin Protection Against Acute Immune-Mediated Glomerulonephritis in Mice. Kidney International. 69(3): 457-463.
Hellman, N.E., Spector, J., Robinson, J., Zuo, X., Saunier, S., Antignac, C., Tobias, J.W., Lipschutz, J.H. 2008. Matrix Metalloproteinase 13 (MMP13) and Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP1), Regulated by the MAPK Pathway, are Both Necessary for MDCK Tubulogenesis. Journal of Biological Chemistry. 283(7): 4272-4282. PMID: 18039671.
Berman, E., Lipschutz, J.M., Bloom, R.D., Lipschutz, J.H. 2008. The Bioethics and Utility of Selling Kidneys for Renal Transplantation. Transplantation Proceedings. 40:1264-1270. PMID: 18589084.
Zuo, X., Guo, W., Lipschutz, J.H. 2009. The Exocyst Protein Sec10 is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro. Molecular Biology of the Cell. 20:2522-2529 (highlighted in “MBC Incytes”). PMID: 19297529.
Park, K.M, Fogelgren, B., Zuo, X., Kim, J., Chung, D.C., Lipschutz, J.H. 2010. Exocyst Sec10 Protects Epithelial Barrier Integrity and Enhances Recovery Following Oxidative Stress, by Activation of the MAPK Pathway. American Journal of Physiology, Renal Physiology. 298(3): F818-826. PMID: 20053792.
Blosser, C., Ayehu, G., Wu, S., LoMagro, R.M., Mallone, E., Brunelli, S.M., Itkin, M., Golden, M., McCombs, P., Lipschutz, J.H. 2010. High Rate of Fistula Placement in a Cohort of Dialysis Patients in a Single Payer System. Hemodialysis International. 14(4):393-397.
Fogelgren, B., Lin, S.Y., Zuo, X., Jaffe, K., Park, K.M., Reichert, R.J., Bell, P.D., Burdine, R.D., Lipschutz, J.H. 2011. The Exocyst Protein Sec10 Interacts with Polycystin-2 and Knockdown Causes PKD-Phenotypes. PLoS Genetics. 7(4):1-17 (e1001361).
Zuo, X., Fogelgren, B., Lipschutz, J.H. 2011. The Small GTPase Cdc42 is Essential for Primary Ciliogenesis In Renal Tubular Epithelial Cells. In Press. Journal of Biological Chemistry.