Role of Matrix Metalloproteinase-2 in Recovery after Tubular Damage in Acute Kidney Injury in Mice

Abstract

Background/Aims: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. Methods: AKI was induced in MMP-2 wild-type (MMP-2^+/+) and MMP-2-deficient (MMP-2^-/-) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2^+/+ mice were also treated with MMP-2/MMP-9 inhibitor. Results: In both MMP-2^+/+ and MMP-2^-/- mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2^+/+ mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2^-/- mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2^+/+ mice. Conclusion: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.

Germacrane sesquiterpenes isolated from the rhizome of Curcuma xanthorrhiza Roxb. inhibit UVB-induced upregulation of MMP-1, -2, and -3 expression in human keratinocytes

“…MMP-1, the key enzyme in aging, is able to hydrolyze type 1 collagen in the ECM on the dermis (Kim et al 2010). MMP-2 is 72 kDa type IV collagenase and gelatinase A, which were activated by MMPs proteinase or ROS (Kaneko et al 2012). MMP-3 degrades collagens types II, III, IV, IX, X, and proteoglycans, fibronectin, laminin, and elastin.…”

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

“…13,[18][19][20] Several MMPs such as MMP-2, MMP-8, and MMP-9 have been implicated in regulating kidney injury and recovery after AKI. [21][22][23][24] However, the role of MMP-7 in the pathogenesis of AKI is completely unknown.…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[94][95][96]292,[323][324][325] These protective mechanisms include the up-regulation of pro-angiogenic factors such as isoform 164 of VEGF-A that protect against capillary rarefaction, and increased expression of matrix metalloproteinases that effect repair and protect against fibrosis by degrading extracellular matrix. 326,327 In addition, short-term exposure to hypoxia leads to increased renal expression of antioxidants such as nuclear factor erythroid 2-related factor 2, hemeoxygenase 1, and metallothionein I that protect against fibrosis and inflammation induced by reactive oxygen species. 94,292,[328][329][330] However, when hypoxia is prolonged, there is an up-regulation of natural antisense HIF-1α that decreases HIF-1α expression by destabilizing its mRNA.…”