title: Age-dependent shifts in renal response to injury relate to altered BMP6/CTGF expression and signaling.
abstract: Age is associated with an increased prevalence of chronic kidney disease (CKD), which, through progressive tissue damage and fibrosis, ultimately leads to loss of kidney function. Although much effort is put into studying CKD development experimentally, age has rarely been taken into account. Therefore, we investigated the effect of age on the development of renal tissue damage and fibrosis in a mouse model of obstructive nephropathy (i.e., unilateral ureter obstruction; UUO). We observed that after 14 days, obstructed kidneys of old mice had more tubulointerstitial atrophic damage but less fibrosis than those of young mice. This was associated with reduced connective tissue growth factor (CTGF), and higher bone morphogenetic protein 6 (BMP6) expression and pSMAD1/5/8 signaling, while transforming growth factor-β expression and transcriptional activity were no different in obstructed kidneys of old and young mice. In vitro, CTGF bound to and inhibited BMP6 activity. In summary, our data suggest that in obstructive nephropathy atrophy increases and fibrosis decreases with age and that this relates to increased BMP signaling, most likely due to higher BMP6 and lower CTGF expression.
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Lucas L
authors: LL
authors: Falke
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Nephrology and Renal Replacement Therapy, Nagoya University, Nagoya, Japan.
authors: Hiroshi
authors: H
authors: Kinashi
authors: Department of Pathology, University Medical Center, Antwerp, Belgium.
authors: Amelie
authors: A
authors: Dendooven
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Roel
authors: R
authors: Broekhuizen
authors: Department of Metabolic Health Research, TNO, Leiden, The Netherlands; and.
authors: Reinout
authors: R
authors: Stoop
authors: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Jaap A
authors: JA
authors: Joles
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Tri Q
authors: TQ
authors: Nguyen
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands; R.Goldschmeding@umcutrecht.nl.
authors: Roel
authors: R
authors: Goldschmeding
mesh_terms: D000367:Age Factors; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C526318:CCN2 protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor
keywords: BMP; CKD; CTGF; UUO; aging