Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice

Yoshimi Takamiya, Kei Fukami, Sho Ichi Yamagishi, Yusuke Kaida, Yosuke Nakayama, Nana Obara, Ryuji Iwatani, Ryotaro Ando, Kiyomi Koike, Takanori Matsui, Yuri Nishino, Seiji Ueda, Mark E. Cooper, Seiya Okuda

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)

Abstract

Background: Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. Methods: Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. Results: Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. Conclusions: Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.

Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalNephrology Dialysis Transplantation
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Keywords

  • albuminuria
  • diabetic nephropathy
  • extracellular matrix
  • MMP-2
  • tubulointerstitial injury

Cite this