Reiser Laboratory

General Information

Jochen Reiser, M.D., Ph.D.
Professor, Medicine / Nephrology
Professor, Cell Biology and Anatomy
Chief, Division of Nephrology and Hypertension
Director, Peggy and Harold Katz Family Drug Discovery Center

Research Interests

• Molecular analysis of proteinuria mechanisms
• Cell biology and drug discovery for kidney podocytes

Keywords and Phrases

• Proteolytic pathways and enzymatic systems regulation
• Cytoskeleton and cell motility
• Podocytes and proteinuria
• Urokinase receptor signaling
• Integrin based adhesion and signaling
• Metabolic flux and control analysis
• TRPC channel biology
• Protein structure

Contact Information

• Office location: Clinical Research Building (CRB)
  1120 NW 14th Street
  Suite 1132 CRB C-211
  Miami, FL 33136
• Tel: (305)-243-2349
  Fax: (305)243-4338
• E-mail: JReiser@med.miami.edu
• Lab Location: Batchelor Bldg., 6th Fl.
  1580 NW 10th Avenue
  Miami, FL 33136
• Tel: (305) 243-4177
•  Fax: (305) 243-4338
• Executive Assistant: Nadia Albelo
  1120 NW 14th Street
  Suite 1185 CRB C-211
  Miami, FL 33136
  Tel: (305) 243-4606
  Fax: (305) 243-4338
  NAlbelo@med.miami.edu

Members

Research

Characterization of glomerular disease as enzymatic disease: Cathepsin L is a protease known to be associated with podocyte damage. We have made the discovery that a novel version of cathepsin L that is located in the podocyte cytoplasm can be responsible for the development of podocyte foot process effacement and proteinuria. A computational approach identified proteolytic targets in podocytes. A series of experiments are underway that characterize the mechanisms of these proteolytic events and classify proteinuric glomerular diseases as enzymatic diseases.

The role of the ion channel TRPC6 in the regulation of podocyte structure and function: In 2005, we have described five families with mutations in the TRPC6 ion channel associated with focal segmental glomerulosclerosis, a disease characterized by progressive kidney failure. We were the first laboratory to show that TRPC6 directly interacts with podocin and nephrin, two key components of the podocyte slit diaphragm. Most recently, we have started to define the role of TRPC6 in the development of common forms of acquired glomerular diseases such as Membranous Glomerulopathy. Eventually, our observations will lead to a more refined understanding of the podocyte TRPC6 ion channel and explore possibilities for reagents targeting TRPC6 dysfunction.

The role of urokinase receptor in podocyte motility and homeostasis. We have shown that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism including lipid dependent activation of αvβ3 integrin.  Mice lacking uPAR are protected from LPS-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin.  Gene transfer studies revealed a prerequisite need for uPAR in podocytes but not in endothelial cells to develop LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes which promotes cell motility and activation of small GTPases cdc42 and Rac1. Blockade of αvβ3 integrin by cyclic RGDfV (Cilengitide) reduces podocyte motility in vitro and proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability and provide a novel rationale for protecting renal function by blocking uPAR signals such as active αvβ3 integrin using cyclic RGDfV.

Defining podocyte metabolism in health and disease: The central metabolism of a cell can determine its short- and long-term structure and function. When a disease state arises, the metabolism (i.e., the transportation of nutrients into the cells, the overall substrate utilization and production, synthesis and accumulation of intracellular metabolites, etc.) is altered in a way that organisms can survive under the disease-state physiology. Recent advances in analytical methods and mathematical tools have led to new approaches to those questions with the concept of computational biology which relies on the integration of experimentation, data processing and modeling. The attempt to formulate current knowledge in mathematical terms has led to the development of several mathematical modeling tools (i.e., metabolic flux analysis, metabolic control analysis, etc.) that helps us to understand an entire biological system from basic structure to dynamic interactions. Using Metabolic Flux analysis in cultured podocytes, grown under various conditions, we are beginning to define the metabolic networks of podocyte and study how metabolic alterations, which occur during injury, can be used to aid in future therapeutic development.

Students can select projects from the following major research areas:

• Cell and molecular biological analysis of TRPC6 in podocytes. This project includes the effects of TRPC6 activation and expression on the regulation of the podocyte actin cytoskeleton. Studies include the analysis of TRPC6 function in cultured podocytes and in mice that have altered levels of TRPC6 or that express mutant TRPC6.
• Cell and structural biological characterization of cytosolic cathepsin L and its cleavage targets. This project includes the functional characterization of cathepsin L action on important podocyte regulatory proteins. A computational screen identified several targets for cathepsin L in the podocyte cytosol that need further chararcterization. We are also working on new inhibitors of cathepsin L using proteina dngene delivery techniques.
• The role of urokinase receptor in podocytes. This research area includes the functional analysis of uPAR as a modifier of beta 3 integrin signaling in podocytes that modulates glomerular filter function.
• Role of podocyte metabolism. Metabolic Flux studies have identified key knots of the podocyte metabolism that are critical for podocyte stress adaptation and survival. Projects are available to characterize nutrient and aminoacid utilization pathways in podocyte health and disease.

Selected Publications

• Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, and Mundel P. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha-3 integrin. J Biol Chem. 2004, 279: 34827-34891
• Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004, 113: 1390-1397
• Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005; 37:739-44.
• Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007;18: 29-36.
• Sever S, Altintas M, Nankoe S, Ko D, Wei C, Henderson J, Kretzler M, Cohen M, del Re E, Erickson A, Kerjaschki D, Rudensky A, Nikolic B and Reiser J. Processing of the GTPase dynamin by extralysosomal cathepsin L defines a mechanism for proteinuric kidney disease J Clin Invest. 2007, 117: 2095-2104.
• Wei C, Möller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Kretzler M, Parrilla R, Bendayan M, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 2007 Dec 16; [Epub ahead of print].
•  Altintas MM, Ulgen KO, Palmer-Toy DE, Shih VE, Kompala DS, Reiser J. 2008. Emerging roles for metabolic engineering: Understanding primitive and complex metabolic models and their relevance to healthy and diseased kidney podocytes. Curr Chem Biol 2:68-82
• Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the anti-proteinuric effect of cyclosporine A. Nat Med. 2008, 14: 931-9388
• Moller CC, Flesche J, Reiser J. Sensitizing the slit diaphragm- role of the ion channel TRPC6 J Am Soc Nephrol 2008 Sept 10; [Epub ahead of print].
• Möller CC, Mangos S, Drummond I, Reiser J. Expression profiles of TRPC1 and TRPC6 orthologs in zebrafish Gene Expr Patterns. 2008 May;8(5):291-6. Epub 2008 Feb 19.