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Internal Medicine Divisions

Matthias Kretzler, M.D.

Research Summary:

The major research focus of my laboratory is on the use of modern molecular biology tools to better understand disease mechanism activated in human renal biopsies. We currently evaluate these novel tools for molecular diagnosis of kidney and transplant failure in international multicenter studies. The longstanding interest in my group has been on glomerular filtration barrier failure. Using cell and molecular biology approaches we have identified novel cell-matrix signaling molecules activated in glomerular failure. Intervening with their function might evolve into a novel therapeutic strategy and we are currently evaluate this approach with small molecule inhibitors in vitro and in vivo and in cell type specific knock out mice.

Link to PubMed Citations

Selected Publications:

Luan F, Trillsch F, Henger A, Eichinger F, Norman S, Appelman H, Kretzler M: A Pilot Study of Gene Expression Based Catagorization of Pancreas Transplant Biopsies. Transplantation, in press.

Sanchez-Nino MD, Sanz AB, Ihalmo P, Lassila M, Holthofer H, Mezzano S, Aros C, Groop PH, Saleem MA, Mathieson PW, Langham R, Kretzler M, Nair V, Lemley K, Nelson RG, Mervaala E, Mattinzoli D, Rastaldi MP, Ruiz-Ortega M, Martin-Ventura JL, Egido J, Ortiz A: The MIF receptor CD74 in diabetic podocyte injury. J Am Soc Nephrol, in press.

Tian Y, Patel JM, Nair V, Martini S, Kretzler M: “Periscope/GQ: A Graph Querying Toolkit.” In the 34th International Conference on Very Large Databases. Auckland , New Zealand , August 24-30, 2008 , demo paper (in press).

Lindenmeyer MT , Rastaldi MP, Ikehata M, Neusser MA, Kretzler M, Cohen CD, Schlondorff D: Endoplasmic Reticulum Stress is Induced by Proteinuria in Human Diabetic Nephropathy and Minimal Change Disease. J Am Soc Nephrol, in press.

Raffetseder U, Rauen T, Djudjaj S, Kretzler M, En-Nia A, Tacke F, Zimmerman HW, Nelson PJ, Frye BC, Floege J, Stefanidis I, Weber C, Mertens PR: Differential regulation of chemokine CCL5 expression in monocytes/macrophages and renal cells by Y-box protein-1. epub PMID, 18800033, 2008

Zhang H, Saha J, Byun J, Schin M, Lorenz M, Kennedy RT, Kretzler M, Feldman EL, Pennathur S, Brosius 3rd FC: Rosiglitazone Reduces Renal and Plasma Markers of Oxidative Injury and Reverses Urinary Metabolite Abnormalities in the Amelioration of Diabetic Nephropathy. Am J Physiol Renal Physiol, epub PMID, 18667486, 2008

Cohen CD, Lindenmeyer MT, Eichinger F, Hahn A, Seifert M, Moll AG, Schmid H, Kiss E, Grone E, Grone HJ, Kretzler M, Werner T, Nelson PJ: Improved elucidation of biological processes linked to diabetic nephropathy by single probe-based microarray data analysis. PLoS ONE, 13, e2937, 2008.

Martini S, Eichinger F, Nair V, Kretzler M: Defining human diabetic nephropathy on the molecular level: Integration of transcriptomic profiles with biological knowledge. Rev Endocr Metab Disord, epub PMID: 18704688, 2008

Wiggin TD, Kretzler M, Pennathur S, Sullivan KA, Brosius FC, Feldman EL: Rosiglitazone Treatment Reduces Diabetic Nephropathy in STZ Treated DBA/2J Mice. Endocrinology, epub, PMID, 18583417, 2008.

Neusser MA, Lindenmeyer MT , Kretzler M, Cohen CD: Genomic analysis in nephrology –towards systems biology and systematic medicine? Nephrol Ther, epub, PMID18586598, 2008.

Shi X, Qu H, Kretzler M, Wu C: The roles of PINCH-2 in regulation of glomerular cell shape change and fibronectin matrix deposition. Am J Physiol Renal Physiol, 295, F253-63, 2008.

Lorz C, Benito-Marin A, Boucherot A, Ucero AC, Rastaldi MP, Henger A, Armelloni S, Santamaria B,Berthier CC, Kretzler M*, Egido J, Ortiz A* (*corresponding authors): Apoptosis gene expression in human diabetic nephropathy: focus on TRAIL. J Am Soc Nephrol, 19, 904-14, 2008.

Ratelade J, Lavin TA, Muda AO, Morisset L, Mollet G, Boyer O, Chen DS, Henger A, Kretzler M, Hubner N, Théry C, Gubler MC, Montagutelli X, Antignac C, Esquivel EL: Maternal Environment Interacts with Modifier Genes to Influence Progression of Nephrotic Syndrome, J Am Soc Nephrol, 19, 1491-9, 2008.

Murphy M, Docherty N, Griffin B, Howlin J, McArdle E, McMahon R, Schmid H, Kretzler M, Droguett A, Mezzano S, Brady H, Furlong F, Godson C, Martin F: IHG-1 amplifies TGF-b1 signaling and is increased in renal fibrosis. J Am Soc Nephrol, 19, 1672-80, 2008.

Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius FC III. From Fibrosis to Sclerosis: Mechanisms of Glomerulosclerosis in Diabetic Nephropathy, Diabetes, 57, 1439-45, 2008.

Wei C, Moeller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Rarrilla R, Bendayan M, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser R: Modification of kidney barrier function by the urokinase receptor. Nat Med 55-63, Jan 14, 2008 .

Sanz AB, Justo P, Sanchez-Niño MD, Blanco-Colio LM, Winkles JA, Kreztler M, Jakubowski A, Blanco J, Egido J, Ruiz-Ortega M, Ortiz A. The cytokine TWEAK modulates renal tubulointerstitial inflammation. J Am Soc Nephrol, 19, 695-703, 2008.

Higgins DF, Kimura, K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial to mesenchymal transition. J Clin Invest. 117, 3810-3820, 2007.

Walsh DW, Roxburgh SA, McGettigan P, Berthier CC, Higgins GD, Kretzler M, Cohen CD, Mezzano S, Brazil DP, Martin F: Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochim Biophys Acta, 1782, 10-21, 2008.

Sever S, Altintas MM, Nankoe SR, Moller CC, Ko D, Wei C, Henderson J, del Re EC, Hsing L, Erickson A, Cohen CD, Kretzler M, Kerjaschki D, Rudensky A, Nikolic B, Reiser J: Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest. 117, 2095-104, 2007.

Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlöndorff D, Cohen CD: Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy. J Am Soc Nephrol, 18, 1765-76, 2007.

Braun GS, Kretzler M, Heider T, Floege J, Holzman LB, Kriz W, Moeller MJ: Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells. J Biol Chem, 282, 22823-33, 2007.

Ihalmo P, Schmid H, Rastaldi MP, Mattinzoli D, Langham RG, Luimula P, Kilpikari R, Lassila M, Gilbert RE, Kerjaschki D, Kretzler M, Holthofer H. Expression of filtrin in human glomerular diseases. Nephrol Dial Transplant, 22, 1903-1909, 2007.

Heller F, Lindenmeyer MT , Cohen CD, Brandt U, Draganovici D, Fischereder M, Kretzler M, Anders HJ, Sitter T, Mosberger I, Kerjaschki D, Regele H, Schlondorff D, Segerer S. : The contribution of B cells to renal interstitial inflammation. Am J Pathol, 170, 457-68, 2007.

Mayer V, Hudkins KL, Heller F, Schmid H, Kretzler M, Brandt U, Anders HJ, Regele H, Nelson PJ, Alpers CE, Schlondorff D, Segerer S: Expression of the chemokine receptor CCR1 in human renal allografts.Nephrol Dial Transplant, 22, 1720-9, 2007.

Möller 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, 18, 29-36, 2007.

Jung KY , Kretzler M, Wu C: Transforming growth factor beta1 regulates PINCH-1-ILK-alpha-parvin complex in glomerular cells. J Am Soc Nephrol, 18, 66-73, 2007.

Barton M, Mullins JJ, Bailey MA and Kretzler M: New role of endothelin receptors for renal protection and survival in hypertension: waiting for clinical trials. Hypertension, 48, 834-7, 2006.

Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner B, Eichinger F, Nitsche A, Kiss E, Bleich M, Groene HJ, Nelson PJ, Schlondorff D, Cohen CD and Kretzler M: Modular activation of NF-kB transcriptional programs in human diabetic nephropathy, Diabetes, 55, 2993-3003, 2006.

Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM, Marsden PA, Pippin J, Shankland S, Rastaldi MP, Cohen CD, Kretzler M, Quaggin SE: Loss of the Tumor Suppressor VHL Leads to de Novo Glomerular Expression of CXCR4 and Rapidly Progressive Glomerulonephritis in Mice. Nature Medicine, 12, 1081-9, 2006.

Patole PS, Pawar RD, Lech M, Zecher D, Schmidt H, Segerer S, Ellwart A, Henger A, Kretzler M, Anders HJ. Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice.Nephrol Dial Transplant, epub, 2006.

Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T, Kretzler M: Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex. Am J Kidney Dis, 48:e27-9, 2006.

Cohen CD, Klingenhoff A, Boucherot A, Nitsche A, Henger A, Brunner B, Schmid H, Merkle M, Saleem MA, Koller KP, Werner T, Gröne HJ, Nelson PJ, Kretzler M: Comparative promoter analysis allows de novo identification of specialized cell junction associated proteins. Proc Natl Acad Sci USA , 103, 5682–5687, 2006.

El-Aouni C, Herbach N, Blattner SM, Henger A, Rastaldi MP, Jarad G, Miner JH, Moeller MJ, St-Arnaud R, Dedhar S, Holzman LB, Wanke R, Kretzler M: Podocyte-specific deletion of Integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol, 17, 1334-44, 2006.

Yasuda Y, Cohen CD, Henger A, Kretzler M: Gene expression profiling analysis in nephrology: towards molecular definition of renal disease. Clin Exp Nephrol, 10, 91-8, 2006.

Segerer S, Draganovic D, Brandt U, Regele H, Schmid H, Henger A, Kretzler M, Nelson P, Kerjaschki D, Schlondorff D: Expression of chemokine receptor CXCR1 in human glomerular disease. Kidney Int, 69, 1765-73, 2006.

Rastaldi MP, Armelloni S, Berra S, Calvaresi N, Corbelli A, Giardion LA, Li M, Wang GQ, Fornasieri A, Villa A, Heikkila E, Soliymani R, Boucherot A, Cohen CD, Kretzler M, Nitsche A, Ripamonti M, Malgaroli A, Pesaresi M, Forloni GL, Schlondorff D, Holthofer H, D’Amico G: Glomerular podocytes contain neuron-like functional synaptic vesicles. Faseb J, 20, 976-8, 2006.

Wornle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M, Blattner S, Bock E, Kretzler M, Grone HJ, Schlondorff D: Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol,168, 370-85, 2006.

Hotchkiss H, Chu TT, Hancock WW, Schroppel B, Kretzler M, Schmid H, Liu Y, Dikman S, Akalin E: Differential Expression of Profibrotic and Growth Factors in Chronic Allograft Nephropathy. Transplantation, 81, 342-349, 2006.

Schmid H, Henger A, Kretzler M: Molecular approaches to chronic renal disease. Curr Opin Nephrol Hypertension, 15, 123-9, 2006.

Pawar RD, Patole PS, Zecher D, Segerer S, Kretzler M, Schlondorff D, Anders HJ:Toll-Like Receptor-7 Modulates Immune Complex Glomerulonephritis.J Am Soc Nephrol, 17, 141-9, 2006.

Cohen CD, Doran PP, Blattner SM, Merkle M, Wang GQ, Schmid H, Mathieson P, Saleem MA, Henger A, Rastaldi MP, and Kretzler M: Sam68-like Mammalian protein 2, identified by digital differential display as expressed by podocytes, is induced in proteinuria and involved in splice site selection of vascular endothelial growth factor.J Am Soc Nephrol, 16, 1958-65, 2005.

Cohen CD, Calvaresi N, Armelloni S, Schmid H, Henger A, Ott U, Rastaldi MP, Kretzler M:CD20-positive infiltrates in human membranous glomerulonephritis. J Nephrol, 18, 328-33, 2005.

Teixeira VPC, Blattner SM, Li M, Anders HJ, Cohen CD, Edenhofer I, Calvaresi N, Merkle M, Rastaldi MP, Kretzler M: Functional consequences of Integrin-linked kinase activation in podocyte damage. Kidney Int, 67,514-523, 2005.

Patole PS, Schubert S, Segerer S, Meßmer A, Khandoga S, Khandoga A, Henger A, Kretzler M, Werner M, Krombach F, Schlöndorff D, Anders HJ: Toll-like receptor-4: Renal cells and bone marrow cells signal for neutrophil recruitment during infective pyelonephritis. Kidney Int, 68, 2582-7, 2005.

Schmid H, Nitschko H, Gerth J, Kliem V, Henger A, Cohen CD, Schlondorff D, Grone HJ, and Kretzler M: Polyomavirus DNA and RNA detection in renal allograft biopsies: results from a European multicenter study. Transplantation, 80, 600-4, 2005.

Yang Y, Guo L, Blattner SM, Mundel P, Kretzler M*, Wu C* (*corresponding authors):Formation and phosphorylation of the PINCH-1- Integrin linked kinase - alpha-parvin complex are important for regulation of renal glomerular podocyte adhesion, architecture and survival.J Am Soc Nephrol, 16, 1966-76, 2005.

Patole PS, Grone HJ, Segerer S, Ciubar R, Belemezova E, Henger A, Kretzler M, Schlondorff D, Anders HJ: Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J Am Soc Nephrol, 16, 1326-38, 2005.

Schmid H, Burg M, Kretzler M, Banas B, Grone HJ, Kliem V: BK virus associated nephropathy in native kidneys of a heart allograft recipient.Am J Trans, 5, 1562-8, 2005.

Dolan V, Murphy M, Sadlier D, Lappin D, Doran P, Godson C, Martin F, O’Meara Y, Schmid H, Henger A, Kretzler M, Droguett A, Mezzano S, Brady H: Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy. Am J Kidney Dis, 45, 1034-9, 2005

Blattner SM, Kretzler M: Integrin-linked kinase in renal disease: Connecting cell-matrix interaction to the cytoskeleton. Curr Opinion Nephrol Hypertension, 14, 404-10, 2005.

Ninichuk V, Gross O, Reichel C, Khandoga A, Pawar RD, Ciubar R, Segerer S, BelemezovaE, Radomska E, Luckow B, de Lema GP, Murphy PM, Gao JL, Henger A, Kretzler M, Horuk R, Weber M, Krombach F, Schlondorff D, Anders HJ: Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease. J Am Soc Nephrol, 16, 977-85, 2005.

Eis V, Luckow B, Vielhauer V, Siveke JT, Linde Y, Segerer S, De Lema GP, Cohen CD, Kretzler M, Mack M, Horuk R, Murphy PM, Gao JL, Hudkins KL, Alpers CE, Grone HJ, Schlondorff D, Anders HJ: Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J Am Soc Nephrol, 15:337-47, 2004.

Segerer S, Banas B, Wornle M, Schmid H, Cohen CD, Kretzler M, Mack M, Kiss E, Nelson PJ, Schlondorff D, Grone HJ: CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Path, 164, 635-49, 2004.

Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Perez de Lema G, Strutz F, Bauer S, Rutz M, Wagner H, Grone HJ, Schlondorff D: Activation of toll-like receptor-9 induces progression of MRL-Fas(lpr) mice. FASEB J, 18, 534-6, 2004.

Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C: Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol, 24, 550-60, 2004.

Esteban V, Lorenzo O, Rupérez M, Suzuki Y, Mezzano S, Blanco J, Kretzler M, Sugaya T, Egido J, Ruiz-Ortega M:Angiotensin II, via AT1 and AT2 receptors and NF- k B pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol, 15, 1514-29, 2004.

Porubsky S, Schmid H, Bonrouhi M, Kretzler M, Malle E, Nelson PJ, Grone HJ:Influence of native and hypochlorite-modified low-density lipoprotein on gene expression in human proximal tubular epithelium. Am J Path, 164, 2175-2187, 2004.

Luckow B, Joergensen J, Chilla S, Li JP, Henger A, Kiss E, Wieczorek G, Roth L, Hartmann N, Hoffmann R, Kretzler M, Nelson PJ, Perez de Lema G, Maier H, Wurst W, Balling R, Pfeffer K, Grone HJ, Schlondorff D, and Zerwes HG: Reduced intragraft mRNA expression of metalloproteinases Mmp3, Mmp12, Mmp13, and Adam8, and diminished transplant arteriosclerosis in Ccr5-deficient mice.Eur J Immunol, 34, 2568-78, 2004.

Schmid H, Cohen CD, Henger A, Schlondorff D, Kretzler M: Gene expression analysis in renal biopsies. Nephrol Dial Transplant, 19, 1347-51 2004.

Anders HJ, Belemezova E, Eis V, Segerer S, Vielhauer V, Perez de Lema G, Kretzler M, Cohen CD, Frink M, Horuk R, Hudkins KL, Alpers CE, Mampaso F, Schlondorff D. Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J Am Soc Nephrol, 15, 1504-13, 2004.

Fischereder M, Kretzler M:New immunosuppressive strategies in renal transplant recipients. J Nephrol, 17, 9-18, 2004.

Henger A, Schmid H, Kretzler M: Gene expression analsis in human renal biopsies: recent developments towards molecular diagnosis of kidney disease. Curr Opin Nephrol Hypertension, 13, 313-8, 2004.

Henger A*, Kretzler M*, Doran P, Bonrouhi M, Schmid H, Kiss E, Cohen CD, Madden S, Porubsky S, Grone EF, Schlondorff D, Nelson PJ, Grone HJ (*equal contribution): Gene expression fingerprints in human tubulo-interstitial inflammation and fibrosis as prognostic markers of disease progression. Kidney Int, 65, 904-17, 2004.

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, 113:1390-7, 2004.

Vielhauer V, Berning E, Eis V, Kretzler M, Segerer S, Strutz F, Horuk R, Gröne HJ, Schlondorff D, Anders HJ: CCR-1 blockade reduces interstitial inflammation and fibrosis in mice with focal segmental glomerular sclerosis and nephrotic syndrome.Kidney Int., 66, 2264-78, 2004.

Banas B, Wornle M, Merkle M, Gonzalez-Rubio M, Schmid H, Kretzler M, Fink M, Perez de Lema G, Schlondorff D: Binding of the chemokine SLC/CCL21 to its receptor CCR7 increases adhesive properties of human mesangial cells. Kidney Int., 66, 2256-63, 2004.

O’Riordan E, Orlova TN, Mei JJ, Butt K, Chander PM, Rahman S, Mya M, Hu R, Momin J, Eng EW, Hampel DJ, Hartman B, Kretzler M, Delaney V, Goligorsky MS: Bioinformatic analysis of the urine proteome of acute allograft rejection. J Am Soc Nephrol, 15:3240-8, 2004.

Ortmann J, Amann K, Brandes RP, Kretzler M, Munter K, Parekh N, Traupe T, Lange M, Lattmann T, Barton M: Role of podocytes for the reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelial inhibition. Hypertension, 44, 974-81, 2004.


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