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Mechanismen der Nephrotoxizität

A lot of substances have nephrotoxic side effects and act as cell stressors as e.g. chemotherapeutica (cisplatin, metabolites of ifosfamide) or mycotoxins. Ochratoxin A (OTA) is a ubiquitous mycotoxin produced by some species of Aspergillus and Penicillium genus acting primarily on the kidney. It is detectable in human blood in low concentration due to normal diet. OTA is frequently supposed to be the causing agent of Balkan endemic nephropathy and of porcine nephropathy. The mechanism of the cell damaging action of these cell stressors often remains largely unknown.

Subject of our studies is:

  • Altered gene expression in human renal cells induced by OTA
  • Posttranscriptional regulation influenced by OTA and other cell stressors
  • Transformation of epithelial cells by OTA and other nephrotoxins
  • Cell death induced by OTA and other nephrotoxins (cisplatin, fumonisins)
  • Transport of OTA across epithelia of the nephron and its uptake into cells studied on MDCK cells. 
  • Effects of OTA on carrier systems of cells of the proximal tubule (OK cells). 
  • Interaction of OTA with chloride channels and cellular pH-homeostasis 
  • Impairment of renal hemodynamics by OTA 
  • Impairment of proximal tubular function by OTA 
  • Impairment of the renal concentrating mechanism by OTA 
  • Impairment of urine acidification by OTA 
  • Interaction of OTA and other nephrotoxins with intracellular signaling pathways 
  • Cytotoxicity of  ifosfamide and its metabolites chloroacetaldeyhde and acrolein on renal cells 
  • Interaction of ifosfamide and its metabolites with intracellular signaling 

Related articles:

2016

Rottkord, U., Röh, C., Ferse, I, Schulz, MC., Rückschloss, U., Gekle, M., Schwerdt, G. and Humpf, HU.: Structure-activity relationship of ochratoxin A and synthesized derivatives: importance of amino acid and halogen moiety for cytotoxicity.Arch. Toxicol. 2016 [abstract]

2014

Hennemeier, I., Humpf, H.U., Gekle, M. and Schwerdt, G.: Role of microRNA29-b in the ochratoxin A-induced enhanced collagen formation in human kidney cells. Toxicology, 324, 116-122, 2014 [abstract]

Benesic, A., Schwerdt, G., Hennemeier, I., Sauvant, C., Mildenberger, S. and Gekle, M.:The nephrotoxic ifosfamide-metabolite chloroacetaldehyde interferes with renal extracellular matrix homeostasis.Cell. Physiol. Biochem., 33, 1106-1116, 2014 [abstract]

Hennemeier, I., M. Gekle and G. Schwerdt: Stress-induced expression and function of the lng non-coding WISP1 transcript lncWISP1 in human renal cells. Acta Physiologica 210 Suppl. 695, 117, 2014

2013

Weidner M., M. Lenczyk, G. Schwerdt, M. Gekle and HU Humpf: Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. Chem Res Toxicol. 26 (3), 347-355, 2013 [abstract]

2012 

Hennemeier, I., HU Humpf, M. Gekle and G. Schwerdt: The food contaminant and nephrotoxin ochratoxin A enhances Wnt1 inducible signaling protein 1 and tumor necrosis factor-α expression in human primary proximal tubule cells. Mol. Nutr. Food Res. 56 (9), 1375–1384, 2012 [abstract]

Weidner, M., T. Welsch, F. Hübner, G. Schwerdt, M. Gekle and HU Humpf: Identification and apoptotic potential of T-2 toxin metabolites in human cells. J. Agric. Food. Chem. 60 (22), 5676-5684, 2012 [abstract]

Hennemeier, I., M. Gekle and G. Schwerdt: Signaling pathways involved in ochratoxin A-induced expression of Wnt1 inducible signaling protein 1 in human kidney cells. Acta Physiologica 204 Suppl. 689, 264, 2012

2011

Hennemeier, I., M. Gekle and G. Schwerdt: Influence of ochratoxin A on gene expression in primary human proximal tubule cells. Acta Physiologica 201 Suppl. 682, 243, 2011

Hennemeier, I., M. Gekle and G. Schwerdt: Ochratoxin A influences the expression of genes involved in renal pathophysiology in primary human proximal tubule cells. Mycotoxin-Workshop Freising, 2011

2009 

Königs, M., D. Mulac, G. Schwerdt, M. Gekle and HU Humpf: Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture. Toxicology 258(2-3), 106-115, 2009 [abstract]

Schwerdt, G., H. Holzinger, M. Königs, HU Humpf and M. Gekle: Effect of ochratoxin A on cell survival and collagen homeostasis in human mesangial cells in primary culture. Food Chem. Toxicol. 47 (1), 209-213, 2009 [abstract]

Schwerdt, G., M. Königs, H. Holzinger, HU Humpf and M. Gekle: Effects of the mycotoxin fumonisin B(1) on cell death in human kidney cells and human lung fibroblasts in primary culture. J. Appl. Toxicol. 29(2), 174-182, 2009 [abstract

2008

Königs, M., G. Schwerdt, M. Gekle and H.U. Humpf: Effects of the mycotoxin deoxynivalenol on human primary hepatocytes. Mol. Nutr. Food Res. 52(7), 830-839, 2008 [abstract]

2007

Königs, M., M. Lenczyk, G. Schwerdt, H. Holzinger, M. Gekle and HU. Humpf: Cytotoxicity, metabolism and cellular uptake of the mycotoxin deoxynivalenol in human proximal tubule cells and lung fibroblasts in primary culture. Toxicology 240, 48-59, 2007 [abstract]

Schwerdt, G., A. Kirchhoff, R. Freudinger, B. Wollny, A. Benesic and M. Gekle: Mesna or cysteine prevents chloroacetaldehyde-induced cell death of human proximal tubule cells. Pediatr. Nephrol. 22 (6), 798-803, 2007 [abstract]

Schwerdt, G.,  H. Holzinger, C. Sauvant, M. Königs, HU. Humpf and M. Gekle: Long-term effects of ochratoxin A on fibrosis and cell death  in human proximal tubule or fibroblast cells in primary culture. Toxicology 232, 57-67 [abstract]

2006

Benesic, A., G. Schwerdt, R. Freudinger, S. Mildenberger, F. Groezinger, B. Wollny, A. Kirchhoff and M. Gekle: Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephrotoxicity. Kidney and Blood Press Res. 29, 280-293 [abstract]

Schwerdt, G., N. Gordjani, A. Benesic, R. Freudinger, B. Wollny, A. Kirchhoff and M. Gekle: Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells. 
Pediatr. Nephrol. 21 (1), 60-67  [abstract]

2005

Benesic, A., G. Schwerdt, S. Mildenberger, R. Freudinger, N. Gordjani and M. Gekle: Disturbed Ca2+-signaling by chloroaecetaldehyde: A possible cause for chronic ifosfamide nephrotoxicity. Kidney Int. 68, 2029-2041 [abstract]

Sauvant, C., H. Holzinger and M. Gekle: Ochratoxin A induces typical signs of nephropathy in proximal tubular cells which are induced by a specific activation pattern of mitogen activiated protein kinases (ERK, JNK, and p38) and modulated by a prototypical anthocyanidin. Proceedings 27th Mycotoxin-Workshop, Dortmund 2005

Knecht, A.,  G. Schwerdt, M. Gekle and H.U. Humpf. Combinatory effects of citrinin and ochratoxin A in human proximal tubule cells. Proceedings 27th Mycotoxin-Workshop, Dortmund 2005

Schwerdt, G.,  R. Freudinger, C. Schuster, F. Weber, O. Thews and M. Gekle. Cisplatin-induced apoptosis is enhanced by hypoxia and by inhibition of  mitochondria in renal collecting duct cells. Toxicol. Sci. 85, 735-742, 2005 
[abstract]

Sauvant, C., H. Holzinger and M. Gekle. The nephrotoxin ochratoxin A induces key parameters of chronic interstitial nephropathy in renal proximal tubular cells. 
Cell. Physiol. Biochem. 15, 125-134, 2005 [abstract]

Weber, F., R. Freudinger, G. Schwerdt and M. Gekle. A rapid screening method to test apoptotic synergisms of ochratoxin A with other nephrotoxic substances.
Toxicol. in Vitro 19, 135-143, 2005 
[abstract]

Gekle, M., C. Sauvant and G. Schwerdt. Ochratoxin A at nanomolar concentrations: A signal modulator in renal cells. Mol. Nutr. Food Res. 49, 118-130, 2005 
[abstract]

Blazer-Yost, B.L., T.A. West, J. Stack, K. Peck, T.F. Lahr and M. Gekle. Effect of the mycotoxin ochratoxin A on  hormone-stimulated ion transport in a cultured model of the renal principal cell. Pflügers Arch., 2005 
[abstract]

Sauvant, C., H. Holzinger and M. Gekle. Proximal tubular toxicity of ochratoxin A is amplified by simulaneous inhibition of  the extracellular regulated kinases 1/2.
J. Pharm. Exp. Ther., 313, 234-241, 2005 
[abstract]

Sauvant, C., H. Holzinger, S. Mildenberger and M. Gekle. Exposure to nephrotoxic ochratoxin A enhances collagen secretion in human renal proximal tubular cells. 
Mol. Nutr. Food Res. 49, 31-37, 2005  [abstract]

2004

Weber, F., G. Schwerdt, R. Freudinger and M. Gekle. Programmed cell death by interaction of ochratoxin A with other nephrotoxins. Mycotox. Res. 19, 20-23, 2004 

Schwerdt, G., R. Freudinger, C. Schuster, S. Silbernagl and M. Gekle. Inhibition of mitochondria and extracellular acidification enhance ochratoxin A-induced apoptosis in renal collecting duct-derived MDCK-C7 cells. Cell. Physiol. Biochem. 14, 47-56, 2004 [abstract] 

Ludwig, T., C. Riethmüller, M. Gekle, G. Schwerdt and H. Oberleithner. Nephrotoxicity of platinum complexes is related to basolateral organic cation transport. Kidney Int. 66, 196-202, 2004 [abstract]

2003

Schwerdt, G., R. Freudinger, C. Schuster, S. Silbernagl and M. Gekle. Inhibition of mitochondria prevents cell death in 
kidney epithelial cells by intra- and extracellular acidification. 
Kidney Int. 63, 1725-1735, 2003 [abstract] 

Seefelder, W., H.U. Humpf, G. Schwerdt, R. Freudinger and M. Gekle. Induction of apoptosis in cultured human proximal tubule cells by fumonisins and fumonisin metabolites. Toxicol. Appl. Pharmacol. 192, 146-153, 2003 [abstract] 

2002

Gekle, M., G. Schwerdt and C. Sauvant. Tubulotoxische Mechanismen am Beispiel von Ochratoxin A. Nieren und Hochdruckkrankheiten 31 (8), 324-328, 2002 

Seefelder, W., G. Schwerdt, R. Freudinger, M. Gekle and H. U. Humpf. Liquid chromatography/electrospray ionisation-mass spectrometry method for the quantification of sphingosine and sphinganine in cell cultures exposed to fumonisins. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 780 , 137, 2002 [abstract] 

2001

Schwerdt, G., R. Freudinger, C. Schuster, S. Silbernagl and M. Gekle. The role of mitochondria and extracellular pH in ochratoxin A-induced apoptosis of human proximale tubule cells. Pflügers Arch. Suppl. 441, R245, 2001 (poster) 

Schwerdt, G, C. Schuster, S. Silbernagl, M. Gareis and Gekle, M. Preliminary results on ochratoxin A concentrations in blood of patients with various kidney diseases in Germany. Mycotoxin Res. 17A (2), 146-149, 2001 (Proceedings 23rd Mycotoxin-Workshop, Vienna 2001) 

Schwerdt, G., F. Weber, R. Freudinger, C. Schuster, S. Silbernagl and M. Gekle. Effect of mitochondrial inhibition and extracellular pH on apoptosis of human proximal tubule cells. J. Am. Soc. Nephrol. 12, A3231, 2001 (poster) 

2000

Benesic, A., S. Mildenberger and M. Gekle. Nephritogenic ochratoxin A interferes with hormonal signalling in immortalized human kidney epithelial cells. Pflügers Arch. 439, 278-287, 2000 [abstract] 

Gekle, M., G. Schwerdt, R. Freudinger, S. Mildenberger, D. Wilfingseder, V. Pollack, M. Dander and H. Schramek. Ochratoxin A induces JNK activation and apoptosis in MDCK-C7 cells at nanomolar concentrations. J. Pharmacol. Exp. Ther. 293, 837-844, 2000 [abstract] 

Eder, S., A. Benesic, R. Freudinger, J. Engert, G. Schwerdt, K. Drumm and M. Gekle. Nephritogenic ochratoxin A interferes with mitochondrial function and pH homeostasis in immortalized human kidney epithelial cells. Pflügers Arch. 440, 521-529, 2000 [abstract] 

Schwerdt, G., R. Freudinger, C. Schuster, S. Silbernagl and M. Gekle. Apoptosis in cultured renal epithelial cells caused by ochratoxin A. Mycotoxin Research 16A, 154-157, 2000 (Proceedings 22nd Mycotoxin-Workshop Bonn 2000)

1999

Schwerdt, G., R. Freudinger, S. Silbernagl and M. Gekle. Ochratoxin A-binding proteins in rat organs and plasma and in different cell lines of the kidney. Toxicology 135, 1-10, 1999 [abstract] 

Benesic, A., S. Eder, C. Sauvant, Schwerdt, G. and M. Gekle. Ochratoxin A induces proliferation of immortalized human kidney epithelial cells at low nanomolar concentrations by interference with cellular Ca2+-homeostasis. Proceedings 21st Mycotoxin-Workshop, Jena 130-138, 1999 

Sauvant, C., S. Silbernagl and M. Gekle. Chronische Exposition von humanen Zellen des proximalen Tubulus mit nanomolaren Konzentrationen von freiem Ochratoxin A führt zu einer verminderten Expression des basolateralen Transportproteins für organische Anionen, OAT1 (Chronic exposure of human proximal tubule cells to nanomolar concentrations of free ochratoxin A leads to decreased expression of the basolateral anion transporter, OAT1) . Proceedings 21st Mycotoxin-Workshop, Jena 234-238, 1999 

Schwerdt, G., R. Freudinger, S. Silbernagl and M. Gekle. Ochratoxin A-induzierte Expressionsänderungen des Tumorsuppressorproteins p53 in Zellen des humanen proximalen Tubulus (Ochratoxin A-induced changes in the expression of the p53 tumor suppressor protein in cells of the human proximal tubule) . Proceedings 21st Mycotoxin-Workshop, Jena 239-244, 1999

Gekle, M., S. Mildenberger, C. Sauvant, D. Bednarczyk, S.H. Wright and W.H. Dantzler. Inhibition of initial transport rate of basolateral organic anion carrier in renal PT by BK and phenylephrine. Am. J. Physiol. (Renal Physiology) 46, F251-F256, 1999 [abstract] 

Schwerdt, G., R. Freudinger, S. Mildenberger, S. Silbernagl and Gekle, M. The nephrotoxin ochratoxin A induces apoptosis in human proximal tubule cells. Cell Biol. Toxicol. 15, 405-415, 1999 [abstract] 

1998

Dahlmann, A., W.H. Dantzler, S. Silbernagl and M. Gekle. Detailed mapping of ochratoxin A reabsorption along the rat nephron in vivo: The nephrotoxin can be reabsorbed in all nephron segments by different mechanisms. J. Pharmacol. Exp. Ther. 286, 157-162, 1998 [abstract] 

Gekle, M., C. Sauvant, G.Schwerdt and S. Silbernagl. Tubulotoxic mechanisms of ochratoxin A. Kidney Blood Press Res 21: 277-279, 1998 [abstract] 

Gekle, M., B. Gassner, R. Freudinger, S. Mildenberger, S. Silbernagl, W. Pfaller and H. Schramek. Characterization of an ochratoxin-A-dedifferentiated and cloned renal epithelial cell line. Toxicol. Appl. Pharmacol. 152, 282-291, 1998 [abstract] 

Sauvant, C., S. Silbernagl and M. Gekle. Exposure of renal proximal-tubule derived cells to naturally occurring concentrations of ochratoxin A preferentially impairs the organic anion transporter OAT1. Proceedings 20th Mycotoxin-Workshop, Detmold 64-68, 1998 

Gekle, M., C. Martinez, S. Mildenberger, R. Freudinger, G. Schwerdt, C. Sauvant and S. Silbernagl. Susceptibility of human kidney cells to the ubiquitous food contaminant ochratoxin A. Proceedings 20th Mycotoxin-Workshop, Detmold 76-80, 1998 

Schwerdt, G., R. Freudinger, S. Silbernagl and M. Gekle. Detection of ochratoxin-A-binding proteins in different rat organs and renal cell lines. Proceedings 20th Mycotoxin-Workshop, Detmold 257-261, 1998 

Sauvant, C., S. Silbernagl and M. Gekle. Exposure to ochratoxin A impairs organic anion transport in proximal-tubule-derived Opossum kidney cells. J. Pharmacol. Exp. Ther. 287, 13-20, 1998 [abstract] 

Schwerdt, G., R. Freudinger, S. Silbernagl and M. Gekle. Apical uptake of radiolabelled ochratoxin A into Madin-Darby canine kidney cells. Toxicology 131, 193-202, 1998 [abstract] 

1997

Zingerle, M., S. Silbernagl and M. Gekle. Reabsorption of the nephrotoxin ohratoxin A along the rat nephron in vivo. J. Pharmacol. Exp. Ther. 280, 220-224, 1997 [abstract] 

Schwerdt, G., M. Gekle, R. Freudinger, S. Mildenberger and S. Silbernagl. Apical-to-basolateral transepithelial transport of ochratoxin A by two subtypes of Madin-Darby canine kidney cells. Biochem. Biophys. Acta 1324, 191-199, 1997 [abstract] 

Bahnemann, E., H.P. Kerling, S. Ensminger, G. Schwerdt, S. Silbernagl and M. Gekle. Renal transepithelial secretion of ochratoxin A in the non-filtering toad kidney. Toxicology 120, 11-17, 1997 [abstract] 

Kuramochi, G., M. Gekle and S. Silbernagl. Ochratoxin A disturbs pH homeostasis in the kidney: increases in pH and HCO3- in the tubules and vasa recta. Pflügers Arch. 434, 392-397, 1997 [abstract] 

Sauvant, C., S. Silbernagl and M. Gekle. Effect of chronic exposure to ochratoxin A on organic anion transport systems in OK cells. Proceedings 19th Int. Mycotoxin-Workshop, München 100-104, 1997 

Schwerdt, G., M. Zingerle, R. Freudinger, M. Gekle and S. Silbernagl. Reabsorptive uptake of ochratoxin A in rat kidney collecting duct and in MDCK-cells. Proceedings 19th Int. Mycotoxin-Workshop, München 95-99, 1997 

Gekle, M., S. Wünsch, G. Kuramochi, R. Freudinger, S. Mildenberger, S. Silbernagl. The renal collecting duct as a target of acute ochratoxin A exposure: Effects on acid-base homeostasis. Proceedings 19th Int. Mycotoxin-Workshop, München 90-94, 1997 

Schramek, H., D. Wilfingseder, V. Pollack, R. Freudinger, S. Mildenberger and M. Gekle. Ochratoxin A-induced stimulation of extracellular signal-regulated kinases 1/2 is associated with Madin-Darby canine kidney-C7 cell dedifferentition. J. Pharmacol. Exp. Ther. 283, 1460-1468, 1997 [abstract] 

1996

Schwerdt, G., K. Bauer, M. Gekle and S. Silbernagl. Accumulation of ochratoxin A in rat kidney in vivo and in cultivated renal epithelial cells in vitro. Toxicology 114, 177-185, 1996 [abstract] 

Gekle, M. and S. Silbernagl. Renal toxicodynamics of ochratoxin A: A pathophysiological approach. Kidney Blood Press. Res. 19, 225-235, 1996. [abstract] 

1995 

Gekle, M., PollockC.A., and S. Silbernagl. Time- and concentration-dependent biphasic effect of ochratoxin A on growth of proximal tubular cells in primary culture. J.Pharmacol.Exp.Ther. 275, 397-404, 1995. [abstract] 

1994

Bauer, K., M. Gekle, and S. Silbernagl. Untersuchungen zur Verteilung von Ochratoxin A in unterschiedlichen Nierenabschnitten. (Distribution of ochratoxin A in different kidney sections) Proceedings 16th Int. Mycotoxin-Workshop, Hohenheim 139-142, 1994. 

Gekle, M. and S. Silbernagl. The role of the proximal tubule in ochratoxin A nephrotoxicity in vivo: toxodynamic and toxokinetic aspects. Renal Physiol Biochem 17:40-49, 1994. [abstract] 

Gekle, M., R. Vogt, H. Oberleithner, and S. Silbernagl. The mycotoxin ochratoxin A deranges pH homeostasis in Madin-Darby canine kidney cells. J. Membrane Biol. 139: 183-190, 1994. [abstract] 

Gekle, M., Mildenberger, S., Freudinger, R., and S. Silbernagl. The mycotoxin ochratoxin A impairs protein uptake in cells derived from the proximal tubule of the kidney (opossum kidney cells). J.Pharmacol.Exp.Ther. 271:1-6, 1994. [abstract] 

Gekle, M., S. Wünsch, H. Oberleithner, and S. Silbernagl. Characterization of two MDCK-cell subtypes as a model system to study principal and intercalated cell properties. Pflügers Arch. 428: 157-162, 1994. [abstract] 

1993

Gekle, M., H. Oberleithner and S. Silbernagl. Ochratoxin A impairs postproximal nephron function in vivo and blocks plasma membrane anion conductance in Madin-Darby canine kidney cells in vitro. Pflügers Arch. 425: 401-408, 1993. [abstract] 

Gekle, M. and S. Silbernagl. Mechanism of ochratoxin A-induced reduction of glomerular filtration rate. J. Pharmacol. Exp. Ther. 276: 316-321, 1993. [abstract] 

Gekle, M., S. Silbernagl, S. Mildenberger and R. Freudinger. Effect on dome formation and uptake of Ochratoxin A in proximal tubule-derived Opossum kidney cell monolayers. Cell Physiol Biochem 3: 68-77, 1993. 

Kontakt

Michael Gekle 
Gerald Schwerdt 
Sigrid Mildenberger 
Marie-Christin Schulz

in Kooperation mit:
Hans Ulrich Humpf  (Institut für Lebensmittelchemie, Universität Münster)


gefördert durch: Deutsche Forschungsgemeinschaft