title: Human bone morphogenetic protein-7 does not counteract aristolochic acid-induced renal toxicity.
abstract: Aristolochic acids (AA) are nephrotoxic and profibrotic agents, leading to chronic kidney disease. As some controversial studies have reported a nephroprotective effect of exogenous recombinant human bone morphogenetic protein (rhBMP)-7 in several models of renal fibrosis, we investigated the putative effect of rhBMP-7 to prevent progressive tubulointerstitial damage after AA intoxication in vitro and in vivo. In vitro, the toxicity of AA on renal tubular cells was demonstrated by an increase in vimentin as well as a decrease in β-catenin expressions, reflecting a dedifferentiation process. Increased fibronectin and interleukin-6 levels were measured in the supernatants. Enhanced α-SMA mRNA levels associated to decreased E-cadherin mRNA levels were also measured. Incubation with rhBMP-7 only prevented the increase in vimentin and the decrease in β-catenin expressions. In vivo, in a rat model of AA nephropathy, severe tubulointerstitial lesions induced by AA after 10 and 35 days (collagen IV deposition and tubular atrophy), were not prevented by the rhBMP-7 treatment. Similarly, rhBMP-7 did not ameliorate the significant increase in urinary concentrations of transforming growth factor-β. In summary, our in vitro data demonstrated a poor beneficial effect of rhBMP-7 to reverse cell toxicity while, in vivo, there was no beneficial effect of rhBMP-7. Therefore, further investigations are needed to confirm the exact role of BMP-7 in progressive chronic kidney disease.
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Marie-Hélène
authors: MH
authors: Antoine
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Frédéric
authors: F
authors: Debelle
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Julie
authors: J
authors: Piccirilli
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Fadoua
authors: F
authors: El Kaddouri
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.|Laboratory of Molecular Physiology (URPhyM), University of Namur, Namur.
authors: Anne-Emilie
authors: AE
authors: Declèves
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Eric
authors: E
authors: De Prez
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Cécile
authors: C
authors: Husson
authors: Laboratory of Physiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors: Frédérique
authors: F
authors: Mies
authors: INSERM U785, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France.
authors: Marie-Françoise
authors: MF
authors: Bourgeade
authors: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels.
authors: Joëlle L
authors: JL
authors: Nortier
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D055419:Bone Morphogenetic Protein 7 / Q000008:administration & dosage / Q000627:therapeutic use*; D002460:Cell Line; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000652:urine; D016896:Treatment Outcome; D014746:Vimentin / Q000096:biosynthesis; D051176:beta Catenin / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D005353:Fibronectins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014746:Vimentin; D051176:beta Catenin; C000228:aristolochic acid I
keywords: Bone morphogenetic protein-7; aristolochic acids; proximal tubular epithelial cell; renal fibrosis; tubular cell dedifferentiation