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Benesic, Andreas; Schwerdt, Gerald; Hennemeier, Isabell; Sauvant, Christoph; Mildenberger, Sigrid and Gekle, Michael (2014): The Nephrotoxic Ifosfamide-Metabolite Chloroacetaldehyde Interferes with Renal Extracellular Matrix Homeostasis. In: Cellular Physiology and Biochemistry, Vol. 33, No. 4: pp. 1106-1116

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Background/Aims: Chronic renal proximal tubule dysfunction after therapy with the antineoplastic agent ifosfamide (IFO) is often attributed to the metabolite chloroacetaldehyde (CAA). Chronic IFO-nephropathy is reported to result in tubulointerstitial fibrosis and inflammation. Methods: To elucidate possible effects of CAA on extracellular matrix homeostasis, we investigated the action of CAA on markers of extracellular matrix (ECM) homeostasis in human proximal tubule cells (RPTEC) by use of direct ELISA for extracellular collagens and gelatin zymography. Results: An increase in type III collagen and a decrease in type IV collagen abundance in the media of RPTEC could be observed after exposure to CAA in clinically relevant concentrations. CAA increased intracellular type III and decreased intracellular type IV collagen. MMP-2 activity was decreased but MMP-9 activity unchanged. The enhanced CAA-induced collagen III formation could be attenuated by the intracellular Ca2+-chelator BAPTA-AM, the PKA-antagonist H-89 and by extracellular acidification. CAA-induced collagen III abundance was enhanced by db-cAMP and IBMX and by protein overload. Conclusions: CAA exerts profibrotic effects on RPTEC dependent on Ca2+ and cAMP/PKA-signaling. These effects are enhanced by additional protein burden and attenuated by acidification. Copyright (C) 2014 S. Karger AG, Basel

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