title: Loss of endogenous bone morphogenetic protein-6 aggravates renal fibrosis.
abstract: Bone morphogenetic protein-6 (BMP-6) suppresses inflammatory genes in renal proximal tubular cells and regulates iron metabolism by inducing hepcidin. In diabetic patients, an increase of myofibroblast progenitor cells (MFPCs), also known as fibrocytes, was found to be associated with decreased BMP-6 expression. We hypothesized that loss of endogenous BMP-6 would aggravate renal injury and fibrosis. Wild type (WT) and BMP-6 null mice underwent unilateral ureteral obstruction. In WT mice, ureteral obstruction down-regulated BMP-6. Obstructed kidneys of BMP-6 null mice showed more casts (1.5-fold), epithelial necrosis (1.4-fold), and brush border loss (1.3-fold). This was associated with more inflammation (1.8-fold more CD45(+) cells) and more pronounced overexpression of profibrotic genes for αSMA (2.0-fold), collagen I (6.8-fold), fibronectin (4.3-fold), CTGF (1.8-fold), and PAI-1 (3.8-fold), despite similar BMP-7 expression. Also, 1.3-fold more MFPCs were obtained from BMP-6 null than from WT mononuclear cell cultures, but in vivo only very few MFPCs were observed in obstructed kidneys, irrespective of BMP-6 genotype. The obstructed kidneys of BMP-6 null mice showed 2.2-fold more iron deposition, in association with 3.3-fold higher expression of the oxidative stress marker HO-1. Thus, ureteral obstruction leads to down-regulation of BMP-6 expression, and BMP-6 deficiency aggravates tubulointerstitial damage and fibrosis independent of BMP-7. This process appears to involve loss of both direct anti-inflammatory and antifibrotic action and indirect suppressive effects on renal iron deposition, oxidative stress, and MFPCs.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Amélie
authors.initials: A
authors.lastname: Dendooven
authors.forename: Olivia
authors.initials: O
authors.lastname: van Oostrom
authors.forename: Dionne M
authors.initials: DM
authors.lastname: van der Giezen
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Leeuwis
authors.forename: Cristel
authors.initials: C
authors.lastname: Snijckers
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D055418:Bone Morphogenetic Protein 6 / Q000172:deficiency* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D015820:Cadherins; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D007501:Iron; D051547:Heme Oxygenase-1