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2015 ; 10
(12
): e0143390
Nephropedia Template TP
gab.com Text
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English Wikipedia
Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from
Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction
#MMPMID26673451
Tveitarås MK
; Skogstrand T
; Leh S
; Helle F
; Iversen BM
; Chatziantoniou C
; Reed RK
; Hultström M
PLoS One
2015[]; 10
(12
): e0143390
PMID26673451
show ga
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.