Glomerular podocytes are essential components of the permeability barrier in the kidney. Damage of podocytes results in proteinuria and, if not reversed within a certain time, can lead to progressive decline of renal function.  In order to tackle glomerular kidney disease, it is crucial to elucidate the regulation of podocyte structure and function at the cellular and molecular level. In my laboratory, we use an integrated approach to address the regulation of podocytes under normal and pathological conditions, involving genetics, cell, molecular and structural biology. Our aim is to define normal and stress-activated pathways in podocytes and to identify molecular targets involved in the early structural changes leading to the development of proteinuria.  Most recently, 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 able to show that TRPC6 is expressed in the podocyte and interacts with podocin and nephrin, two key components of the glomerular slit diaphragm previously implicated in proteinuric kidney disease. Eventually, our observations will lead to a more refined understanding of the podocyte and pave the way for the development of anti-proteinuric and podocyte-protective therapeutics.

Lab Members
Mehmet M. Altintas, Ph.D., Research Fellow in Medicine email maltintas@partners.org, phone (617) 724-6478, fax (617) 726-5669.

Changli Wei, M.D., Ph.D., Research Fellow in Medicine email cwei@partners.org, phone (617) 726-5662, fax (617) 726-5669.

Clemens C. Möller, M.Sc., Research Associate in Medicine email cmoeller@partners.org, phone (617) 724-6478, fax (617) 726-5669.

Mélanie Becker, B.Sc., Visiting Student, phone (617) 724-6478, fax (617) 726-5669.

Selected References
(1) 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 (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. May 27th, 2005;doi:10.1038/ng1592.

(2) Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P (2005) Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner. J Clin Invest. 115:1188-1198.

(3) Reiser J, Mundel P. (2004) Danger signaling by glomerular podocytes defines a novel function of inducible B7-1 in the pathogenesis of nephrotic syndrome. J Am Soc Nephrol. 15:2246-2248.

(4) 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 (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 113:1390-1397.

(5) Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, Mundel P (2004) Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem. 279:34827-34832.

(6) Schwarz K, Simons M, Reiser J, Saleem M, Faul C, Kriz W, Shaw A, Holzman L, Mundel P (2001) Podocin is a raft-associated component of the glomerular slit diaphragm that interacts with CD2AP and nephrin. J Clin Invest. 108:1621-1629.

(7) Reiser J, Pixley FJ, Hug A, Kriz W, Smoyer WE, Stanley ER, Mundel P (2000) Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases. Kidney Int. 57:2035-2042.

(8) Reiser J, Kriz W, Kretzler M, Mundel P (2000) The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 11:1-8.

(9) Kobayashi N, Reiser J, Kriz W, Kuriyama R, Mundel P (1998) Nonuniform microtubular polarity established by CHO1/MKLP1 motor protein is necessary for process formation of podocytes. J Cell Biol. 28:1961-1970.