title: Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction.
abstract: Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Tveitarås
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Trude
authors.initials: T
authors.lastname: Skogstrand
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Sabine
authors.initials: S
authors.lastname: Leh
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Frank
authors.initials: F
authors.lastname: Helle
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Bjarne M
authors.initials: BM
authors.lastname: Iversen
authors.affiliation: Inserm UMR 702, Université Pierre et Marie Curie, Paris VI, Paris, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Center for Cancer Biomarkers, CCBIO, University of Bergen, Bergen, Norway.
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Reed
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.|Department of Medical Cellbiology, Uppsala University, Uppsala, Sweden.|Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Hultström
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D006869:Hydronephrosis / Q000209:etiology* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D020778:Matrix Metalloproteinase 2